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7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 122
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089
CENTRAL NERVOUS SYSTEM INFECTIONS
Lectures 36-40
FALL 2012
Ateef Qureshi
Department of Microbiology
St Georges University
School of Medicine
LEARNING OBJECTIVES
At the end of this series of lectures you should be able to
1 Understand the terminology and anatomy of CNS in relation to infectious disease
2 Describe the routes of entry reservoirs and predisposing factors associated with various
infectious agents
3 Compare and contrast meningitis encephalitis myelitis meningoencephalitis brain
abscesses and empyema on the basis of symptoms and microbes involved
4 Explain mechanisms of pathogenesis and virulence factors of the infectious agents of CNS
5 Discuss immediate symptoms and complications of viral and bacterial agents on the CNS
6 Identify a syndrome and probable causative agent on the basis of CSF profiles
7 Understand the differences between normal infectious agents and the prions
REFERENCES
Murray Rosenthal amp Pfaller (2009) Medical Microbiology 6 th EditionChapter 21 Staphylococci p209-210
Chapter 22 Streptococci p233-242
Chapter 25 Listeria p255-258
Chapter 29 Neisseria p296-299
Chpater 30 Enterobacteriaceae p303 313
Chapter 34 Hemophilus p343-348
Chapter 42 Spirochetes p405-419
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Chapter 51 Papovaviruses p499-502
Chapter 53 Human Herpes viruses p517-539
Chapter 56 Picornaviruses p553-560
Chapter 58 Paramyxoviruses p571-579
Chapter 60 Rhabdoviruses Filoviruses and Bornaviruses p593-597
Chapter 62 Togaviruses and Flaviviruses p609-620
Chapter 63 Arenaviruses and Bunyaviruses p621-625
Chapter 66 Prions p661-665
Chapter 68 Pathogenesis of Fungal Diseases p679-682 684 686-688
INTRODUCTION
Given proper opportunity and environment hundreds of microorganisms are capable of infecting
the human Central Nervous System which includes bacteria viruses fungi protozoa and
parasites Depending upon the actual site of CNS involvement specific clinical pictures emerge
which are described as Meningitis Encephalitis meningoencephalitis myelitis abscesses and
empyema These infections are among the most serious as they may kill the patients quicklyhowever those who survive will have a life-long impairment of one kind or the other These
range from minor discomforts physical disabilities and psychological problems to behavioral
changes Modern antimicrobial therapies have reduced the serious outcomes but they still range
from 8-10 which is unacceptably high Therefore prompt diagnosis and medical help is
essential to maximize the positive outcome of these infections
The brain and the spinal cord are suspended in the cerebrospinal fluid (CSF) which are
surrounded by three layers of meninges Pia mater and the arachnoid mater (Leptomeninges)
and the dura mater (pachymeninges) These structures are provided further protection frominjury and infection by the skull and the vertebral column However this leaves very little space
for any inflammation or swelling to occur Infections do cause inflammation and swelling of the
brain or the spinal cord which can lead to dramatic changes in the intracranial pressure resulting
in serious damage or death
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The Blood-Brain Barrier-including the endothelial cells lining the brain capillaries and are
cemented together by intracellular tight junctions-provide a barrier for micro-organisms and toxic
substances It also impedes the passage of the antibodies and antibiotics into the CSF resulting
in poor prognosis
Fenestratedendothelium
B-CSF-B
Thin Basement
Membrane
B-B-B B-CSF-B
Blood VesselICAMJunctions
Thick
BasementMembrane
Brain-CSF-B
Choroid plexus
epithelium
copyAQureshi S10
Comparison ofBlood-Brain Blood-CSF and Brain-CSF Barriers
Low antibody littl eno phagocytes and complement
B-B-B
CSFBrain
Gap Junctions
It is the entry and replication of the infectious agents that results in many different outcomes of
disease syndromes We will be studying only the very common and prominent infectious agentsand their role in the diseases of the CNS For these lectures we will focus the organisms that
are not covered in detail at other areas of this course The list of chapters and reading
references are only for your convenience to find the related information
Organ System approach in Medical Microbiology provides a framework and prospectiveThree organ systems are closed systemsBone and JointsVascularThe Central Nervous SystemInfections of these are associated with an increased morbidity and mortality
These systems are normally sterile and have no normal biota
Central Nervous System (CNS) InfectionsNo direct communication with the external environment (Blood Brain Barrier)Pathogens reach CNS either by direct extension from a contiguous structure or byhematogenous dissemination from a distant siteIn order to institute appropriate empiric therapy it is critical to know the normal biota and mostcommon pathogens associated with each of these distant sites
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TerminologyMeningitis- infection of the CNS coveringsEncephalitis- infection of brain parenchyma
Myelitis- infection of spinal cordMeningoencephalomyelitis - infection of many areas of brainAbscess- localized pockets of infection in spinal cord or brainEmpyema- epidural or subepidural abscess
Epidemiologic ConsiderationsPatient demographics- age immune statusDisease pattern- acute or chronicExposure history- exposure bites etcEpidemiology- geographic location season outbreaksEtiology of infection- bacterial viral fungal or protozoan
ENCEPHALITES OF VIRAL ETIOLOGY ENCEPHALITES OF VIRAL ETIOLOGY ENCEPHALITES OF VIRAL ETIOLOGY ENCEPHALITES OF VIRAL ETIOLOGY
Virus Geographic
Distribution
Age Group Predominant
Season
Herpes Virus 1amp2 All All None
West Nile Virus All Older adults Summer-Fall
EEE Virus Atlantic amp GulfCoast and Great
Lakes
Children Summer-Fall
WEE Virus Western US ampCanada
Infants amp Older adults Summer-Fall
California
Encephalitis Virus
Midwest amp NE US
S Canada
Older children Summer-Fall
Enteroviruses All Infants amp children Summer
Varicella-ZosterVirus
All Children ampImmunocompromised
Winter
Modified from Table 61-3 page 593 Schaecterrsquos Mechanisms of Microbial Diseases 4th Edition2007 A Qureshi S2010
Entry Replication and Spread
Hematogenous (Important for abscesses)
Meningococci from respiratory epitheliumWest Nile virus through insect biteRubella virus through Transplacental transmission
NeuralRabies peripheral nerves to nerve axons to ganglia and spinal cord to brainHuman Herpes viruses 1-3 through nerves
Direct inoculation through trauma or injuryPenetrating head trauma and surgery
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Most common- Staph aureusImmunodeficient or HIV infections- Nocardia Aspergillus Candida
Most likely through Choroid plexus as it is highly vascularized inflammation may increase entryinto CNSDirect extension
Infections of teeth middle ear or mastoids or sinuses
Most common etiologyAerobic and anaerobic streptococciBacteroidesEnterobacteriaceaePsudomadsFusibacteriumPeptococcus
Etiology depends upon location of the source of infectionMouth- mixed biotaLungs- Streptococci Fusibaterium Corynebacterium Peptococcus spHeart- Strep viridans Staph aureusUrinary tract- Enterobacteriaceae Pseudomonas
Wounds- Staph aureus
CNS SyndromesMeningitis
Acute Meningitis- viral or bacterialChronic Meningitis- fungi and tubercle bacilli
Encephalitis- viralMyelitis- viralBrain Abscesses
Acute Brain Abscess- generally poly microbialChronic Brain Abscess- tubercle bacilli fungi and protozoa
MeningitisInfection of the membranes and fluid surrounding the brain and spinal cord (spinalmeningitis) causing inflammation of the meninges
MeningismGroup of Symptoms and signs associated with the inflammation
HeadacheNuchal rigidityNausea and vomitingPhotophobia
Tests for MeningismDemonstrate inability to flex the neck and touch the chin to the chest
Demonstrate inability to oppose the nose with the kneesTripod sign- inability to sit without making a tripod with handsKernigrsquos sign- patientrsquos leg can not be straightened because of hamstring spasmBrudzinskirsquos neck sign- patient retracts the legs when neck is liftedSymptoms associated with MeningitisDepend upon age microorganism and the route to meninges
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Early symptoms (nonspecific)FeverMalaiseAches and painsNauseaVomiting
Headache
HALL MARKS of Meningitis
Symptoms associated with MeningitisDiagnosis of CNS infectionsCerebrospinal Fluid
Chemical and cellular analysisCulturePCR
FEATURES OF CSF
Etiology Leukocytes
(mm3)
Neutrophils
Glucose
(mgdL)
Protein
(mgdL)
Normal 0-6 0 40-80 20-50
Meningitis
Acute Bacterial
gt1000 gt50 0-10 gt100
Viral 10-1000Usually lt300
High for 24hrs then lt50
40-80 50-100
Chronic Mycobact
amp Fungal
100-500 lt10 le40 gt100
(Mycobact)
50-100
(Fungal)
Encephalitis Viral 10-500 High for 24
hrs then lt50
40-80 50-100
BrainAbscess
Bacterial
Fungal
10-100 lt50 40-80 50-100
10-500 RBCs in HHV-1 Infection A Qureshi S2010
Neuroimaging
Helpful in partial differentiation of viral encephalitisJapanese B virus grey matter involvementNipah virus multiple small white matter lesionsHuman herpes virus-1 hemorrhagesAbscesses and Empyema differentiation
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MeningitisInflammation of the meninges occurs due to viral or bacterial infectionsAseptic
Over 50 of the cases are due to a variety of virusesRest of the cases are due to bacteria with special growth requirements or slow growers
CAUSES OF ASEPTIC ASEPTIC ASEPTIC ASEPTIC MENINGITIS
Viruses Bacteria
Common Enteroviruses
Arboviruses
HHV-2
Borrelia burgdorferi
Inadequately treated bacterial
meningitis
Uncommon Mumps
HHV-5 (CMV)
HHV-6
HIV
Mycobacterium tuberculosis
Leptospira sp
Micoplasma pneumoniae
Incidence varies with the region
Modified from Neurol Clin 2008 26635
A Qureshi S10
Viral Infections of CNS
Viruses use at least two pathways to enter the CNSHematogenous (most common)Neural
Through Olfatory nerve- HHV-1amp2Intra-axonal through neuron route- Rabies
Direct injuryViral infections range from meningitis to myelitis
Viral Meningitis Common causes of Aseptic meningitis
Enteroviruses ( ECHO) coxsackie and poliovirusHerpes virus and other viruses are less common
Mumps virus meningitis is a complication of infectionCSF findings
Glucose ndashnormalProtein- moderately highWBC count- increased predominantly lymphocytes
Gram stain- NO BACTERIA
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EnterovirusesEnteroviruses belong to family PicornavirideaNaked small (25-30 nm) icoshedral virusesResistant to pH 3-9 detergents and heatContain single-stranded positive polarity RNA
Transfecting viruses
Baltimore Class IVa RNA replication in cytoplasmMost viruses are CytolyticOver 63 serotypes involved in meningitisPoliovirus has only 3 serotypes and may cause meningitis to myelitisEradicated from the Western Hemisphere through OPV
More than 90 of viral meningitis cases are due to EnterovirusesOther syndromes caused by enteroviruses include
Hand-foot and mouth diseaseHerpanginaMyocarditisPleurodynia
Acute hemorrhagic conjunctivitis
Clinical syndromes are determined byVirus class and serotypeTissue tropismInfectious dosePortal of entryPatient age sex Immune competence
EpidemiologyWorldwide distributionHumans are the only reservoir
Asymptomatic infections are commonShow seasonality
Temperate climates- Summer to Fall (water)Tropical climates- year-round (fecal-oral)Infants and children MOST susceptible
Please refer to Murray et al (6 th Ed)Box 56-4 p 556
PoliovirusesMember of family PicornaviridaeSame viral characters as that of EnterovirusesSpreads through fecal-oral route by consuming contaminated food and waterThrough direct contact with infected stool or throat secretions
Symptoms common to those of meningeal irritationHeadache fever nuchal rigidity followed by weakness in one or more extremities
Clinical syndromeAcute Flaccid Paralysis due to infection of anterior horn of grey matter
PathogenesisInfects enterocytes of the GI tractTransverses intestinal wall through basement membrane
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Moves into gut-associated lymphoid tissue eg Peyerrsquos patches (site of primaryreplication)Resulting viremia seeds peripheral tissue virus enters the neurons of the peripheralnervous system that innervates the peripheral tissues and the virus traffics to the CNSusing retrograde axonal transport
(Lancaster and Pfeiffer 2010)
Outcomes of infectionInapparent infections
95 asymptomatic virus in RESDiagnosis by virus isolation from feces and oropharynx and by specific serumantibodies
Abortive polio (minor illness)- flu like symptomsSimilar to any systemic viral infection
Polio encephalitis- RARENon-paralytic polio (aseptic meningitis)
Similar to other enteroviral meningitis
Paralytic polio (lt2 of cases)Viral spread is normally restricted due to
Limited replication of virus in peripheral neuronsInsufficient retrograde axonal transport in peripheral neuronsInnate resistance through IFN α β production
When these barriers are breeched the out come will be paralytic polioSpinal - flaccid paralysis due lysis of the anterior horn cellsBulbar - paralysis of cranial nerve IX and X medullarrespiratory centers
PreventionInactivated vaccine
Formalized Salk vaccine injected im
Local antibody is not producedMostly used in Western Hemisphere (where polio is considered eradicated)
Please see Table 56-2 in Murray et al 6 th Ed p 561 Live oral vaccine
Sabin vaccine is stable at room temperature with MgCl2Produces secretory antibodiesVirus can spread to contacts and enhance herd immunity and may causeparalytic polio (~1 in 4 million)
Please see Table 56-2 in Murray et al 6 th Ed p 561
Meningitis (Continued)
Septic (as opposed to viral Aseptic) Caused by bacteria onlyAssociated with high Mortality and SeverityEtiology is AGE dependent
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CAUSES OF SEPTIC SEPTIC SEPTIC SEPTIC MENINGITIS
AGE Most common Others
Birth to 3 months Streptococcus agalactiae Escherichia coli L monocytogenes
3 to 60 months Streptococcuspneumoniae
Neisseria meningitidis
H influenzae type b
gt 60 months Streptococcuspneumoniae
Neisseria meningitidis
L monocytogenes
Other Gram negative
organisms
Any age (cranial
surgery)
Staphylococcus aureus
Any age
(immunosuppressed)
L monocytogenes
Other Gram negatives
(including P aeroginosa)
Bacterial Infections of CNSOver 25 infectious agents involvedSevere life threatening infections requiring prompt diagnosis and treatmentSeptic meningitis (Bacterial meningitis)Bacterial invasion into CNS
Invasion from nearby siteMiddle ear or chronic sinusitis
Spread from a distant siteHematogenous invasion
Direct introductionRARE sometimes the source cannot be identified
Bacterial MeningitisNeonates- Strep agalactiae Coliforms and Listeria monocytogenesInfants- Streptococcus pneumoniae Neisseria meningitidis and H influenzaeChildren- Strep pneumoniae N meningitidis and Listeria monocytogenes Streptococcus pneumoniae most common except neonatesMore than 75 of total cases are caused by N meningitidis Strep pneumoniae and Hinfluenzae combined
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CAUSES OF SEPTIC SEPTIC SEPTIC SEPTIC MENINGITIS
AGE Most common Others
Birth to 3 months Streptococcus agalactiae Escherichia coli L monocytogenes
3 to 60 months Streptococcuspneumoniae
Neisseria meningitidis
H influenzae type b
gt 60 months Streptococcuspneumoniae
Neisseria meningitidis
L monocytogenes
Other Gram negative
organisms
Any age (cranial
surgery)
Staphylococcus aureus
Any age
(immunosuppressed)
L monocytogenes
Other Gram negatives
(including P aeroginosa)
Bacterial Virulence FactorsNeisseria meningitidis
Capsule IgA protease pili and endotoxinHaemophilus influenzae
Capsule IgA protease pili and endotoxin Streptococcus pneumoniae
Capsule and IgA protease only
Neisseria meningitidisGram negative coffee bean shaped intracellular (PMNs) exclusively human pathogenMany members of the genus are commensals of upper respiratory tractAbout 30 of the population may transiently carry N meningitidis Responsible for more than 75 cases of septic meningitis ( Reported by Dr Jungkind) Transmission is via droplet inhalationMore than 13 of the cases occur in the first five years of ageHigh morbidity and mortality ~50 survivors have neurologic or other sequelae
DiagnosisClinical signs- rash (Tumbler test) sepsis fever nuchal rigidityCSF tap- protein glucose and WBC count
Culture- fastidious organism requires 5-10 CO2
Blood or CSF sample- plate on chocolate agarNasopharyngeal swab- plate on to Modified Martin-Thayer agar
Contains antibiotics to inhibit normal biotaRapid techniques
Latex agglutinationPCR
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PreventionTetravalent vaccine composed of Groups A C Y and W135 (Group B is weaklyimmunogenic)
Protection is group specificProtection is limited to ~3 yearsVaccination does not protect from carriage of the organism
Vaccine is poorly immunogenic for infants under 2 years of age
Streptococcus agalactiae Beta hemolytic Taxos A resistant Group B streptococcusNormal female genital organism (~40 colonized))60 mortality for babies who develop meningitis during the first week of life
Premature birth is an important risk factorNeonates
Lethargy fever sepsis and respiratory distressChildren and adults
Puerperal fever at delivery and other skin and soft tissue infections
Streptococcus pneumoniaeGram positive lancet shaped alpha hemolytic Taxos P sensitive cocci (Optochin)Part of normal flora of 20 adults and gt75 healthy childrenMOST COMMON cause of bacterial meningitisHighest cause of infantile meningitisMortality rate for pneumococcal meningitis is ~25Neurological sequelae is ~50
In elderly it may follow pneumoniaMiddle ear infectionsSinusiPathogenesis (Braun et al2002 J Clin Invest 10919-27)
Pathogenesis
Hydrogen peroxide- due to absence of catalase large amounts accumulate and enhanceapoptosisPneumolysin
pore forming toxinPotent neurotoxin can trigger cellular apoptosis
Pathogenesis (Guikel et al2003 PNAS10014363-14367)In mouse models invasion can occur through nasopharynx (not hematogenous)Teichoic and lipoteichoic acids of cell wall mediate binding to the gangliosides expressedon the neuronsSubsequent travel is then via retrograde axonal transport along olfactory neurons
Haemophilus influenzae
Gram negative fastidious encapsulated pleomorphic organismsSpread via blood from respiratory tract to the brainInfection opportunity between 4 months to 3 yearsGreater risk of permanent neurologic damage than any other bacterial meningitisVaccines made with type B capsular polysaccharide
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Enterobacteriaceae
Escherichia coli K1Gram negative facultative anaerobesDuring pregnancy increased colonization of K1 strain with 8 mortality
Spreads from nasopharynx to the meningesEnterobacteriaceae Symptoms
lt1 month old- irritability lethargy vomiting lack of appetite and seizures4-18 months- nuchal rigidity tense fontanels and feverOlder children amp adults- headache vomiting confusion lethargy seizures and feve
Interactions during meningitis
Escherichia coli GI respiratory orgenitourinary tract
bloodstream
Slide kindly provided by Dr J Rayner
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Klebsiella pneumoniaeGram negative rodsHigh incidence in cockroach infested areasEarly onset- lt3 days- 2nd only to GBS
(leukopenia and neutropenia)Late onset- 8-28 days-2nd only to Staphylococcus
(leukocytosis and neutrophilia)Symptoms
Lethargy poor feeding little cry fever scleremaCulture from blood CSF urineC-reactive protein positive
Listeria monocytogenesGram positive non spore forming aerobic motile rodsEpidemiology
Food-borne (dairy and deli)Soil water decaying vegetation
Human intestines may be reservoir
2-12 humans carry the organismCan be transmitted to the baby during delivery (may cause spontaneous abortions)Pathogenesis
Grows in macrophagesReleases ldquoInternalinrdquo- as a cell attachment molecule trigger entryListeriolysin- protein that helps in movement within the cellHemolysin- pore-forming toxin Allows escape from phagosome to the phagosoleUses host cell actin to move to the new cells
DiagnosisIntracellular gram positive rods in macrophages and neutrophilsCSF culture- looks like β-Strep but catalase + and ldquotumblerdquo
Slide is kindly provided by Dr Rayner
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Spirochetes Infections of CNSTreponema pallidum
Early stages are infectious and no CNS involvementTakes about 10 year or longer for non treated cases
Neurosyphilis is the Tertiary stage of the disease and no longer infectiousDelayed hypersensitivity is part of the pathologic mechanism of tissue damageCommonly found in different tissues of the body as ldquoGummasrdquoInfection of CNS is via meningovascular routeSpirochetes Infections of CNSSymptoms
CNS degenerative changes resulting in mental changesMay have frank psychosisShuffling gait ldquotabes dorsalisrdquo
DiagnosisSpinal fluid may be helpfulElevated WBCs and protein
VDRL positive
Leptospira interogans Animals are reservoirsSpreads through animal urine contaminated water and food (survives weeks in water)No body of water in the US is free from itSensitive to Acid pH drying and soap~100 casesyearSewer workers miners veterinarians and meat packers are at risk Spirochetes Infections of CNSSymptoms
Incubation 7-13 days (range 5 days - 4 weeks)
Bacteremic phase- influenza like symptoms and fever (bacteria NOW enter the CNS)2 nd Phase - ~3+weeksHeadache with ldquoasepticrdquo meningitisSometimes hemodynamic collapse
DiagnosisBlood cultureCSF analysis and cultureRise in antibody between acute and convalescent stages
Borrelia burgdorferi~15 Neurologic abnormalities rarely fatal
Starts with a tick biteLarge spirochetes- 02x10-30 micromSpirochetes Infections of CNS
SymptomsClassic ldquobullrsquos eyerdquo rash fever joint pain meningeal irritation2nd Stage- dissemination system wide3rd Stage- mild neurologic or frank encephalitis
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DiagnosisLoose irregular spirals Silver or immunoflourescent stainDifficult to cultureCDC recommends antibody screen using ELISA
Fungal Infections of CNSDisseminate hematogenously from a remote site of infection (oropharynx or lung)Create multiple areas of infection within brain and other organsCan cause abscessesMeningoencephalitis occurs early by vascular invasion by fungusCan see secondary thrombosis cerebral infarction and hemorrhages
Common fungiCandida albicansCryptococcus neoformansHistoplasma capsulatumAspergillus fumigatus
DiagnosisAntibody studiesCXRCandida- forms granulomatus reaction Yeast forms seen with silver stainCryptococcus- fungi appear like encapsulated spheres Capsules can be seen bymucicarmine stain Histoplasma- CT scan Aspergillus- branching hyphae classical appearance
Please revisit your notes on Respiratory fungal infections by Dr Lennon
Encephalitis
EtiologyViral
Herpes viruses enteroviruses arboviruses rabies virus HIV HTLV-1Paramyxoviruses (mumps rubeola virus and arenaviruses)
Bacterial (RARE)Exceptions Legionella pneumoniae Borrelia burgdorferi Treponema pallidum
FungalCryptococcus neoformans
ParasiticPlasmodium falciparum Trypanosomes
MyelitisAcute inflammation of the spinal cord
Depending upon virus this can lead to flaccid paralysisSymptoms
HeadacheFeverIrritation followed by
Weakness of one or more extremitiesEtiology
Poliovirus was the leading cause before vaccinationWest Nile virus is the most significant after 2000
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Defined as inflammation of brain parenchymaEncephalitis is considered clinically a more severe syndrome than viral meningitisSymptoms
HeadacheFever
Altered consciousness-lethargy to confusion and comaBehavioral and speech disturbanceSeizures
Arboviruses Arthropod-borne viral infectionsDistributed worldwideTransmitted by mosquitoes and ticksSporadic and epidemic encephalitisSeizures are generally the complications in children
All arboviruses are enveloped viruses with icosahedral nucleocapsid and contain a transfecting RNA
Major families of arboviruses (Togaviridae and Flaviviridae )Togaviridae
Belongs to Baltimore Class IVbEarly and late proteins madeVirus buds at the plasma membrane
TogaviridaeVenezuelan Equine Encephalitis (VEE)Togaviridae (alphavirus)
Spread through Culex and Aedes mosquitoesSymptoms
Prodrome- fever chills weakness headache myalgia (due to viral replication )Rapid progression- nuchal rigidity confusion somnolence seizure in 50 of cases andcoma (due to spread through microvascular permeability of brain then cell-to-celloccurs via axon and dendrites )NO DEATHS in humans 80 mortality in horses
Eastern Equine Encephalitis (EEE)Common in North AmericaSpreads through Aedes and Culiseta spHumans are dead-end hosts but Aedes may spread from horse to human
Clinical symptoms similar to that of VEEHIGH MORTALITY in humans
Western Equine Encephalitis (WEE)Spreads through Culex and CulisetaCommon in rural areas of US in summer monthsFatality rate 3-4 death in 1-2 days Children have a 30 chance of CNS sequelae
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Pathophysiology of Equine EncephalitidesDefuse CNS involvementNeutrophils and macrophages infiltrate brain parenchyma causing focal necrosis and spottydemyelinationVascular inflammation with endothelial proliferation and small vessel thrombosis
EEELarge number of active virus entering in brain parenchymaEffects the perikaryon and dendrites of neurons with minimal glial cell infiltration
WEEDamage mediated by large number of immunologically active cells that enterbrainCell death by apoptosis primarily in the glial and inflammatory cells
FlaviviridaeBelongs to Baltimore class IVaPolyprotein is translated first which cleaves into many individual proteinsVirus buds inside cytoplasmic vesicles and the virus is released through
exocytosis
St Louis Encephalitis virus (SLE)Epidemiology
Transmitted by culex mosquitoesOvert infection depends upon
Efficiency of replication at extra neural sitesDegree of viremiaAge of the host
PathophysiologyVirus enters through BBB (astrocyte complex)
Or cross fenestrated endothelium (choroid plexus)Symptoms
Mortality 2-20 (higher in elderly)Malaise and fever only 20 develop sequelae (irritability memory loss movementdisorders motor deficits)Seizures and coma COMMONNo chronic illness
Japanese B Encephalitis virus (JBE)Epidemiology
Spread through Culex mosquitoesIncubation 4-14 days
Rural areas of AsiaSeptember 2010 India 319 deaths and Nepal 5 deaths
SymptomsViral prodrome- fever by 2nd weekEncephalitis syndrome with tremors NOT seizuresLow CSF IgGIgM ratio= higher death rate
West Nile Encephalitis virus (WNV)Epidemiology
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Wild birds are reservoir spreads through Aedes mosquitoes3-15 fatalVery RARE person to person transmission
SymptomsViral prodrome with maculopapular rash on trunk and extremitiesHeadache HIGH fever nuchal rigidity stupor tremor and seizures paralysis
BunyaviridaeAt least 200 different viruses included in this groupEnveloped viruses containing single-stranded negative polarity segmented (3) RNASpreads through mosquitoes ticks and flies
California Encephalitis virusLa Crosse virus
RhabdoviridaeLyssavirus RabiesStructure
Bullet shaped virusSingle-stranded negative polarity RNA
Helical nucleocapsid in an envelope5 proteins- NPMG and L
Surface glycoprotein attaches to cell receptors including Acetylcholine receptor atneuromuscular junctions
PathophysiologyViral entry into the cell is via endocytosisVirus has a preference for nerve and salivary gland cells (travels via axons to CNS)Spreads from brain to salivary glands kidneys and conjunctival cells (virus in tears )
EpidemiologyEstimated 35000-50000 cases worldwide
Highest in Asia ~90 casesEndozoonotic all warm blooded animals are susceptible
Urban- dogs and catsSylvatic- wildlife
SymptomsIncubation 20-90 days may extend to a yearNonspecific ndash general malaise fever headache (tingling pain and weakness at the bitsite)Progressive - neurologic symptoms including insomnia confusion slight or partialparalysis agitation hypersalivation dysphagia (hydrophobia)Paralytic ndashdisorientation stupor
Death within days after symptoms (~7 days)Diagnosis
Saliva- virus isolation RT-PCRSerum and CSF for rabies antibodies (FA and ELISA)Brain tissue- Negri bodies Babes nodules consisting of glial cells
TreatmentPrevention
Wash all wounds with soap and water
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1 dose of immune globulin and 4 doses of vaccine on days 137 amp14 days + 2boosters on days 0 and 3
New recommendations by CDC published on Mar 18 2010
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010(MMWR VOL59RR2 MAR 18 2010)
NOT PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent (eg povidine-iodinesolution) should be used to irrigate the wounds
Human rabies
immune globulin(HRIG)
Administer 20 IUkg body weight If anatomicallyfeasible the full dose should be infiltrated around and
into the wound(s) and any remaining volume shouldbe administered at an anatomical site (intramuscular
[IM]) distant from vaccine administration
Vaccine Human diploid cell vaccine (HDCV) or purified chickembryo cell vaccine (PCECV) 10 mL IM (deltoid but
never in the gluteal region) 1 each on days 0 3 7 and
14(For immunocompromised 5 shots)
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010
(MMWR VOL59RR2 MAR 18 2010)
PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent such as povidine-iodinesolution should be used to irrigate the wounds
HRIG HRIG should not be administered
Vaccine HDCV or PCECV 10 mL IM (deltoid but never in the
gluteal area) 1 each on days 0 and 3
For persons with immunosuppression rabies PEPshould be administered using all 5 doses of vaccine on
days 0 3 7 14 and 28
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Other virus infections of the CNSArenaviridae - Lymphocytic ChoriomeningitisTogaviridae- Rubella virusHerpesviridae - Human Herpes virus 1-8Retroviridae - HIV-1Other virus infections of the CNS
Papovaviridae - Polyoma virus (JC virus)-PML (Progressive Multifocal Leukoencephalopathy)Viral DNA in majority of healthy humansMultifocal signs including hemiparesis visual loss seizures dementia personalitychanges and gait problemsCharacteristic white matter lesions common in posterior occipital area
Paramyxoviridae - Mumps viruses and Measles- SSPE (Subacute Sclerosing Pan Encephalitis)Slow fatal condition after more than 10 years of measlesWorldwide more common in boys (31) than girlsBehavior changes in school age childrenFulminant course- 10 of cases death in 3 monthsChronic course- death in 4-10 years
Brain Abscess and EmpyemaLocalized bacterial infection of brain parenchyma and subdural or epidural spacesPressure from accumulation of exudates may permanently damage the brain tissueMay be fatal if not treated properlyAbscess
Fixed boundariesEmpyema
Lack of definable shape or sizeBrain Abscess
Symptoms
Usually are rapid and associated with their locationHeadacheChanges in mental status- drowsiness to comaGeneralized seizure
Fungal brain abscessDisseminated hematogenously from remote site ( lungs or oropharynx)Create multiple areas of infection within brainMeningoencephalitis occurs early by vascular invasionEtiology
Aspergillus Cryptococcus Candida
Transmissible Spongiform EncephalopathiesPrion is an abnormal isomer of normal host proteinNO NUCLEIC ACID presentReplicate without provoking antibody or inflammatory responseAre resistant to some inactivation methods used for bacteria and viruses (70 alcohol X-raysand UV light etc)Sensitive to autoclaving and bleachDisease confined to the CNS and may take decades to manifestCan be inherited (~15) of cases)
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PathogenesisNormal PrPc- glycoprotein with secondary structures dominated by Alpha helixPrion protein PrPSc- glycoprotein with secondary structures dominated by Beta-pleats When PrPSc molecules comes in contact with the normal PrPc molecule the normal PrPc changes into the abnormal PrPSc
Modified protein aggregates in neurons as myeloid plaques
Spongy appearance of cerebrum is due to the formation of vacuoles in the cortex andcerebellum
Spread of PrionsSporadic- no apparent causeInherited - through autosomal dominant traitIngestion - infected food cannibalism
Kuru-incubation ~20 yearsInvolves progressive trunchal shaking and unsteady gait Death within 3-24 months
Medical events- (Iatrogenic) through surgery organs etc
Creutzfeld Jekob Disease (CJD)Most common prion human diseasePeak incidence 55-65 years but can affect teenagersNo treatmentSymptoms
Insidious mental deteriorationEarly cerebellar and visual problemsSevere dementia in 6 monthsBrain and lower motor neuron involvementCases of CJD have been due to
Infected corneal transplantsReused improperly sterilized brain surgery equipment
Pituitary hormone injections derived from cadaversAccidental cuts during autopsies or surgeries
Bovine Variant of CJDBSE re-emerged in 1996 with progressive neurodegenerative disease resulting in patient deathNormally bovine but crossed to humans as Mad Cow DiseaseDiagnosis
Biopsy of BrainSpongiform encephalopathyAccumulation of abnormally folded protein
Sporadic diseaseCSF- no cells
CNS InfectionsThis was by no means a complete inventory of infectious agents involvedThere are many more however we discussed ONLY the very common and frequent infectionsThe original Mad Cow
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Chapter 51 Papovaviruses p499-502
Chapter 53 Human Herpes viruses p517-539
Chapter 56 Picornaviruses p553-560
Chapter 58 Paramyxoviruses p571-579
Chapter 60 Rhabdoviruses Filoviruses and Bornaviruses p593-597
Chapter 62 Togaviruses and Flaviviruses p609-620
Chapter 63 Arenaviruses and Bunyaviruses p621-625
Chapter 66 Prions p661-665
Chapter 68 Pathogenesis of Fungal Diseases p679-682 684 686-688
INTRODUCTION
Given proper opportunity and environment hundreds of microorganisms are capable of infecting
the human Central Nervous System which includes bacteria viruses fungi protozoa and
parasites Depending upon the actual site of CNS involvement specific clinical pictures emerge
which are described as Meningitis Encephalitis meningoencephalitis myelitis abscesses and
empyema These infections are among the most serious as they may kill the patients quicklyhowever those who survive will have a life-long impairment of one kind or the other These
range from minor discomforts physical disabilities and psychological problems to behavioral
changes Modern antimicrobial therapies have reduced the serious outcomes but they still range
from 8-10 which is unacceptably high Therefore prompt diagnosis and medical help is
essential to maximize the positive outcome of these infections
The brain and the spinal cord are suspended in the cerebrospinal fluid (CSF) which are
surrounded by three layers of meninges Pia mater and the arachnoid mater (Leptomeninges)
and the dura mater (pachymeninges) These structures are provided further protection frominjury and infection by the skull and the vertebral column However this leaves very little space
for any inflammation or swelling to occur Infections do cause inflammation and swelling of the
brain or the spinal cord which can lead to dramatic changes in the intracranial pressure resulting
in serious damage or death
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The Blood-Brain Barrier-including the endothelial cells lining the brain capillaries and are
cemented together by intracellular tight junctions-provide a barrier for micro-organisms and toxic
substances It also impedes the passage of the antibodies and antibiotics into the CSF resulting
in poor prognosis
Fenestratedendothelium
B-CSF-B
Thin Basement
Membrane
B-B-B B-CSF-B
Blood VesselICAMJunctions
Thick
BasementMembrane
Brain-CSF-B
Choroid plexus
epithelium
copyAQureshi S10
Comparison ofBlood-Brain Blood-CSF and Brain-CSF Barriers
Low antibody littl eno phagocytes and complement
B-B-B
CSFBrain
Gap Junctions
It is the entry and replication of the infectious agents that results in many different outcomes of
disease syndromes We will be studying only the very common and prominent infectious agentsand their role in the diseases of the CNS For these lectures we will focus the organisms that
are not covered in detail at other areas of this course The list of chapters and reading
references are only for your convenience to find the related information
Organ System approach in Medical Microbiology provides a framework and prospectiveThree organ systems are closed systemsBone and JointsVascularThe Central Nervous SystemInfections of these are associated with an increased morbidity and mortality
These systems are normally sterile and have no normal biota
Central Nervous System (CNS) InfectionsNo direct communication with the external environment (Blood Brain Barrier)Pathogens reach CNS either by direct extension from a contiguous structure or byhematogenous dissemination from a distant siteIn order to institute appropriate empiric therapy it is critical to know the normal biota and mostcommon pathogens associated with each of these distant sites
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TerminologyMeningitis- infection of the CNS coveringsEncephalitis- infection of brain parenchyma
Myelitis- infection of spinal cordMeningoencephalomyelitis - infection of many areas of brainAbscess- localized pockets of infection in spinal cord or brainEmpyema- epidural or subepidural abscess
Epidemiologic ConsiderationsPatient demographics- age immune statusDisease pattern- acute or chronicExposure history- exposure bites etcEpidemiology- geographic location season outbreaksEtiology of infection- bacterial viral fungal or protozoan
ENCEPHALITES OF VIRAL ETIOLOGY ENCEPHALITES OF VIRAL ETIOLOGY ENCEPHALITES OF VIRAL ETIOLOGY ENCEPHALITES OF VIRAL ETIOLOGY
Virus Geographic
Distribution
Age Group Predominant
Season
Herpes Virus 1amp2 All All None
West Nile Virus All Older adults Summer-Fall
EEE Virus Atlantic amp GulfCoast and Great
Lakes
Children Summer-Fall
WEE Virus Western US ampCanada
Infants amp Older adults Summer-Fall
California
Encephalitis Virus
Midwest amp NE US
S Canada
Older children Summer-Fall
Enteroviruses All Infants amp children Summer
Varicella-ZosterVirus
All Children ampImmunocompromised
Winter
Modified from Table 61-3 page 593 Schaecterrsquos Mechanisms of Microbial Diseases 4th Edition2007 A Qureshi S2010
Entry Replication and Spread
Hematogenous (Important for abscesses)
Meningococci from respiratory epitheliumWest Nile virus through insect biteRubella virus through Transplacental transmission
NeuralRabies peripheral nerves to nerve axons to ganglia and spinal cord to brainHuman Herpes viruses 1-3 through nerves
Direct inoculation through trauma or injuryPenetrating head trauma and surgery
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Most common- Staph aureusImmunodeficient or HIV infections- Nocardia Aspergillus Candida
Most likely through Choroid plexus as it is highly vascularized inflammation may increase entryinto CNSDirect extension
Infections of teeth middle ear or mastoids or sinuses
Most common etiologyAerobic and anaerobic streptococciBacteroidesEnterobacteriaceaePsudomadsFusibacteriumPeptococcus
Etiology depends upon location of the source of infectionMouth- mixed biotaLungs- Streptococci Fusibaterium Corynebacterium Peptococcus spHeart- Strep viridans Staph aureusUrinary tract- Enterobacteriaceae Pseudomonas
Wounds- Staph aureus
CNS SyndromesMeningitis
Acute Meningitis- viral or bacterialChronic Meningitis- fungi and tubercle bacilli
Encephalitis- viralMyelitis- viralBrain Abscesses
Acute Brain Abscess- generally poly microbialChronic Brain Abscess- tubercle bacilli fungi and protozoa
MeningitisInfection of the membranes and fluid surrounding the brain and spinal cord (spinalmeningitis) causing inflammation of the meninges
MeningismGroup of Symptoms and signs associated with the inflammation
HeadacheNuchal rigidityNausea and vomitingPhotophobia
Tests for MeningismDemonstrate inability to flex the neck and touch the chin to the chest
Demonstrate inability to oppose the nose with the kneesTripod sign- inability to sit without making a tripod with handsKernigrsquos sign- patientrsquos leg can not be straightened because of hamstring spasmBrudzinskirsquos neck sign- patient retracts the legs when neck is liftedSymptoms associated with MeningitisDepend upon age microorganism and the route to meninges
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Early symptoms (nonspecific)FeverMalaiseAches and painsNauseaVomiting
Headache
HALL MARKS of Meningitis
Symptoms associated with MeningitisDiagnosis of CNS infectionsCerebrospinal Fluid
Chemical and cellular analysisCulturePCR
FEATURES OF CSF
Etiology Leukocytes
(mm3)
Neutrophils
Glucose
(mgdL)
Protein
(mgdL)
Normal 0-6 0 40-80 20-50
Meningitis
Acute Bacterial
gt1000 gt50 0-10 gt100
Viral 10-1000Usually lt300
High for 24hrs then lt50
40-80 50-100
Chronic Mycobact
amp Fungal
100-500 lt10 le40 gt100
(Mycobact)
50-100
(Fungal)
Encephalitis Viral 10-500 High for 24
hrs then lt50
40-80 50-100
BrainAbscess
Bacterial
Fungal
10-100 lt50 40-80 50-100
10-500 RBCs in HHV-1 Infection A Qureshi S2010
Neuroimaging
Helpful in partial differentiation of viral encephalitisJapanese B virus grey matter involvementNipah virus multiple small white matter lesionsHuman herpes virus-1 hemorrhagesAbscesses and Empyema differentiation
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MeningitisInflammation of the meninges occurs due to viral or bacterial infectionsAseptic
Over 50 of the cases are due to a variety of virusesRest of the cases are due to bacteria with special growth requirements or slow growers
CAUSES OF ASEPTIC ASEPTIC ASEPTIC ASEPTIC MENINGITIS
Viruses Bacteria
Common Enteroviruses
Arboviruses
HHV-2
Borrelia burgdorferi
Inadequately treated bacterial
meningitis
Uncommon Mumps
HHV-5 (CMV)
HHV-6
HIV
Mycobacterium tuberculosis
Leptospira sp
Micoplasma pneumoniae
Incidence varies with the region
Modified from Neurol Clin 2008 26635
A Qureshi S10
Viral Infections of CNS
Viruses use at least two pathways to enter the CNSHematogenous (most common)Neural
Through Olfatory nerve- HHV-1amp2Intra-axonal through neuron route- Rabies
Direct injuryViral infections range from meningitis to myelitis
Viral Meningitis Common causes of Aseptic meningitis
Enteroviruses ( ECHO) coxsackie and poliovirusHerpes virus and other viruses are less common
Mumps virus meningitis is a complication of infectionCSF findings
Glucose ndashnormalProtein- moderately highWBC count- increased predominantly lymphocytes
Gram stain- NO BACTERIA
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EnterovirusesEnteroviruses belong to family PicornavirideaNaked small (25-30 nm) icoshedral virusesResistant to pH 3-9 detergents and heatContain single-stranded positive polarity RNA
Transfecting viruses
Baltimore Class IVa RNA replication in cytoplasmMost viruses are CytolyticOver 63 serotypes involved in meningitisPoliovirus has only 3 serotypes and may cause meningitis to myelitisEradicated from the Western Hemisphere through OPV
More than 90 of viral meningitis cases are due to EnterovirusesOther syndromes caused by enteroviruses include
Hand-foot and mouth diseaseHerpanginaMyocarditisPleurodynia
Acute hemorrhagic conjunctivitis
Clinical syndromes are determined byVirus class and serotypeTissue tropismInfectious dosePortal of entryPatient age sex Immune competence
EpidemiologyWorldwide distributionHumans are the only reservoir
Asymptomatic infections are commonShow seasonality
Temperate climates- Summer to Fall (water)Tropical climates- year-round (fecal-oral)Infants and children MOST susceptible
Please refer to Murray et al (6 th Ed)Box 56-4 p 556
PoliovirusesMember of family PicornaviridaeSame viral characters as that of EnterovirusesSpreads through fecal-oral route by consuming contaminated food and waterThrough direct contact with infected stool or throat secretions
Symptoms common to those of meningeal irritationHeadache fever nuchal rigidity followed by weakness in one or more extremities
Clinical syndromeAcute Flaccid Paralysis due to infection of anterior horn of grey matter
PathogenesisInfects enterocytes of the GI tractTransverses intestinal wall through basement membrane
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Moves into gut-associated lymphoid tissue eg Peyerrsquos patches (site of primaryreplication)Resulting viremia seeds peripheral tissue virus enters the neurons of the peripheralnervous system that innervates the peripheral tissues and the virus traffics to the CNSusing retrograde axonal transport
(Lancaster and Pfeiffer 2010)
Outcomes of infectionInapparent infections
95 asymptomatic virus in RESDiagnosis by virus isolation from feces and oropharynx and by specific serumantibodies
Abortive polio (minor illness)- flu like symptomsSimilar to any systemic viral infection
Polio encephalitis- RARENon-paralytic polio (aseptic meningitis)
Similar to other enteroviral meningitis
Paralytic polio (lt2 of cases)Viral spread is normally restricted due to
Limited replication of virus in peripheral neuronsInsufficient retrograde axonal transport in peripheral neuronsInnate resistance through IFN α β production
When these barriers are breeched the out come will be paralytic polioSpinal - flaccid paralysis due lysis of the anterior horn cellsBulbar - paralysis of cranial nerve IX and X medullarrespiratory centers
PreventionInactivated vaccine
Formalized Salk vaccine injected im
Local antibody is not producedMostly used in Western Hemisphere (where polio is considered eradicated)
Please see Table 56-2 in Murray et al 6 th Ed p 561 Live oral vaccine
Sabin vaccine is stable at room temperature with MgCl2Produces secretory antibodiesVirus can spread to contacts and enhance herd immunity and may causeparalytic polio (~1 in 4 million)
Please see Table 56-2 in Murray et al 6 th Ed p 561
Meningitis (Continued)
Septic (as opposed to viral Aseptic) Caused by bacteria onlyAssociated with high Mortality and SeverityEtiology is AGE dependent
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CAUSES OF SEPTIC SEPTIC SEPTIC SEPTIC MENINGITIS
AGE Most common Others
Birth to 3 months Streptococcus agalactiae Escherichia coli L monocytogenes
3 to 60 months Streptococcuspneumoniae
Neisseria meningitidis
H influenzae type b
gt 60 months Streptococcuspneumoniae
Neisseria meningitidis
L monocytogenes
Other Gram negative
organisms
Any age (cranial
surgery)
Staphylococcus aureus
Any age
(immunosuppressed)
L monocytogenes
Other Gram negatives
(including P aeroginosa)
Bacterial Infections of CNSOver 25 infectious agents involvedSevere life threatening infections requiring prompt diagnosis and treatmentSeptic meningitis (Bacterial meningitis)Bacterial invasion into CNS
Invasion from nearby siteMiddle ear or chronic sinusitis
Spread from a distant siteHematogenous invasion
Direct introductionRARE sometimes the source cannot be identified
Bacterial MeningitisNeonates- Strep agalactiae Coliforms and Listeria monocytogenesInfants- Streptococcus pneumoniae Neisseria meningitidis and H influenzaeChildren- Strep pneumoniae N meningitidis and Listeria monocytogenes Streptococcus pneumoniae most common except neonatesMore than 75 of total cases are caused by N meningitidis Strep pneumoniae and Hinfluenzae combined
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CAUSES OF SEPTIC SEPTIC SEPTIC SEPTIC MENINGITIS
AGE Most common Others
Birth to 3 months Streptococcus agalactiae Escherichia coli L monocytogenes
3 to 60 months Streptococcuspneumoniae
Neisseria meningitidis
H influenzae type b
gt 60 months Streptococcuspneumoniae
Neisseria meningitidis
L monocytogenes
Other Gram negative
organisms
Any age (cranial
surgery)
Staphylococcus aureus
Any age
(immunosuppressed)
L monocytogenes
Other Gram negatives
(including P aeroginosa)
Bacterial Virulence FactorsNeisseria meningitidis
Capsule IgA protease pili and endotoxinHaemophilus influenzae
Capsule IgA protease pili and endotoxin Streptococcus pneumoniae
Capsule and IgA protease only
Neisseria meningitidisGram negative coffee bean shaped intracellular (PMNs) exclusively human pathogenMany members of the genus are commensals of upper respiratory tractAbout 30 of the population may transiently carry N meningitidis Responsible for more than 75 cases of septic meningitis ( Reported by Dr Jungkind) Transmission is via droplet inhalationMore than 13 of the cases occur in the first five years of ageHigh morbidity and mortality ~50 survivors have neurologic or other sequelae
DiagnosisClinical signs- rash (Tumbler test) sepsis fever nuchal rigidityCSF tap- protein glucose and WBC count
Culture- fastidious organism requires 5-10 CO2
Blood or CSF sample- plate on chocolate agarNasopharyngeal swab- plate on to Modified Martin-Thayer agar
Contains antibiotics to inhibit normal biotaRapid techniques
Latex agglutinationPCR
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PreventionTetravalent vaccine composed of Groups A C Y and W135 (Group B is weaklyimmunogenic)
Protection is group specificProtection is limited to ~3 yearsVaccination does not protect from carriage of the organism
Vaccine is poorly immunogenic for infants under 2 years of age
Streptococcus agalactiae Beta hemolytic Taxos A resistant Group B streptococcusNormal female genital organism (~40 colonized))60 mortality for babies who develop meningitis during the first week of life
Premature birth is an important risk factorNeonates
Lethargy fever sepsis and respiratory distressChildren and adults
Puerperal fever at delivery and other skin and soft tissue infections
Streptococcus pneumoniaeGram positive lancet shaped alpha hemolytic Taxos P sensitive cocci (Optochin)Part of normal flora of 20 adults and gt75 healthy childrenMOST COMMON cause of bacterial meningitisHighest cause of infantile meningitisMortality rate for pneumococcal meningitis is ~25Neurological sequelae is ~50
In elderly it may follow pneumoniaMiddle ear infectionsSinusiPathogenesis (Braun et al2002 J Clin Invest 10919-27)
Pathogenesis
Hydrogen peroxide- due to absence of catalase large amounts accumulate and enhanceapoptosisPneumolysin
pore forming toxinPotent neurotoxin can trigger cellular apoptosis
Pathogenesis (Guikel et al2003 PNAS10014363-14367)In mouse models invasion can occur through nasopharynx (not hematogenous)Teichoic and lipoteichoic acids of cell wall mediate binding to the gangliosides expressedon the neuronsSubsequent travel is then via retrograde axonal transport along olfactory neurons
Haemophilus influenzae
Gram negative fastidious encapsulated pleomorphic organismsSpread via blood from respiratory tract to the brainInfection opportunity between 4 months to 3 yearsGreater risk of permanent neurologic damage than any other bacterial meningitisVaccines made with type B capsular polysaccharide
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Enterobacteriaceae
Escherichia coli K1Gram negative facultative anaerobesDuring pregnancy increased colonization of K1 strain with 8 mortality
Spreads from nasopharynx to the meningesEnterobacteriaceae Symptoms
lt1 month old- irritability lethargy vomiting lack of appetite and seizures4-18 months- nuchal rigidity tense fontanels and feverOlder children amp adults- headache vomiting confusion lethargy seizures and feve
Interactions during meningitis
Escherichia coli GI respiratory orgenitourinary tract
bloodstream
Slide kindly provided by Dr J Rayner
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Klebsiella pneumoniaeGram negative rodsHigh incidence in cockroach infested areasEarly onset- lt3 days- 2nd only to GBS
(leukopenia and neutropenia)Late onset- 8-28 days-2nd only to Staphylococcus
(leukocytosis and neutrophilia)Symptoms
Lethargy poor feeding little cry fever scleremaCulture from blood CSF urineC-reactive protein positive
Listeria monocytogenesGram positive non spore forming aerobic motile rodsEpidemiology
Food-borne (dairy and deli)Soil water decaying vegetation
Human intestines may be reservoir
2-12 humans carry the organismCan be transmitted to the baby during delivery (may cause spontaneous abortions)Pathogenesis
Grows in macrophagesReleases ldquoInternalinrdquo- as a cell attachment molecule trigger entryListeriolysin- protein that helps in movement within the cellHemolysin- pore-forming toxin Allows escape from phagosome to the phagosoleUses host cell actin to move to the new cells
DiagnosisIntracellular gram positive rods in macrophages and neutrophilsCSF culture- looks like β-Strep but catalase + and ldquotumblerdquo
Slide is kindly provided by Dr Rayner
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Spirochetes Infections of CNSTreponema pallidum
Early stages are infectious and no CNS involvementTakes about 10 year or longer for non treated cases
Neurosyphilis is the Tertiary stage of the disease and no longer infectiousDelayed hypersensitivity is part of the pathologic mechanism of tissue damageCommonly found in different tissues of the body as ldquoGummasrdquoInfection of CNS is via meningovascular routeSpirochetes Infections of CNSSymptoms
CNS degenerative changes resulting in mental changesMay have frank psychosisShuffling gait ldquotabes dorsalisrdquo
DiagnosisSpinal fluid may be helpfulElevated WBCs and protein
VDRL positive
Leptospira interogans Animals are reservoirsSpreads through animal urine contaminated water and food (survives weeks in water)No body of water in the US is free from itSensitive to Acid pH drying and soap~100 casesyearSewer workers miners veterinarians and meat packers are at risk Spirochetes Infections of CNSSymptoms
Incubation 7-13 days (range 5 days - 4 weeks)
Bacteremic phase- influenza like symptoms and fever (bacteria NOW enter the CNS)2 nd Phase - ~3+weeksHeadache with ldquoasepticrdquo meningitisSometimes hemodynamic collapse
DiagnosisBlood cultureCSF analysis and cultureRise in antibody between acute and convalescent stages
Borrelia burgdorferi~15 Neurologic abnormalities rarely fatal
Starts with a tick biteLarge spirochetes- 02x10-30 micromSpirochetes Infections of CNS
SymptomsClassic ldquobullrsquos eyerdquo rash fever joint pain meningeal irritation2nd Stage- dissemination system wide3rd Stage- mild neurologic or frank encephalitis
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DiagnosisLoose irregular spirals Silver or immunoflourescent stainDifficult to cultureCDC recommends antibody screen using ELISA
Fungal Infections of CNSDisseminate hematogenously from a remote site of infection (oropharynx or lung)Create multiple areas of infection within brain and other organsCan cause abscessesMeningoencephalitis occurs early by vascular invasion by fungusCan see secondary thrombosis cerebral infarction and hemorrhages
Common fungiCandida albicansCryptococcus neoformansHistoplasma capsulatumAspergillus fumigatus
DiagnosisAntibody studiesCXRCandida- forms granulomatus reaction Yeast forms seen with silver stainCryptococcus- fungi appear like encapsulated spheres Capsules can be seen bymucicarmine stain Histoplasma- CT scan Aspergillus- branching hyphae classical appearance
Please revisit your notes on Respiratory fungal infections by Dr Lennon
Encephalitis
EtiologyViral
Herpes viruses enteroviruses arboviruses rabies virus HIV HTLV-1Paramyxoviruses (mumps rubeola virus and arenaviruses)
Bacterial (RARE)Exceptions Legionella pneumoniae Borrelia burgdorferi Treponema pallidum
FungalCryptococcus neoformans
ParasiticPlasmodium falciparum Trypanosomes
MyelitisAcute inflammation of the spinal cord
Depending upon virus this can lead to flaccid paralysisSymptoms
HeadacheFeverIrritation followed by
Weakness of one or more extremitiesEtiology
Poliovirus was the leading cause before vaccinationWest Nile virus is the most significant after 2000
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Defined as inflammation of brain parenchymaEncephalitis is considered clinically a more severe syndrome than viral meningitisSymptoms
HeadacheFever
Altered consciousness-lethargy to confusion and comaBehavioral and speech disturbanceSeizures
Arboviruses Arthropod-borne viral infectionsDistributed worldwideTransmitted by mosquitoes and ticksSporadic and epidemic encephalitisSeizures are generally the complications in children
All arboviruses are enveloped viruses with icosahedral nucleocapsid and contain a transfecting RNA
Major families of arboviruses (Togaviridae and Flaviviridae )Togaviridae
Belongs to Baltimore Class IVbEarly and late proteins madeVirus buds at the plasma membrane
TogaviridaeVenezuelan Equine Encephalitis (VEE)Togaviridae (alphavirus)
Spread through Culex and Aedes mosquitoesSymptoms
Prodrome- fever chills weakness headache myalgia (due to viral replication )Rapid progression- nuchal rigidity confusion somnolence seizure in 50 of cases andcoma (due to spread through microvascular permeability of brain then cell-to-celloccurs via axon and dendrites )NO DEATHS in humans 80 mortality in horses
Eastern Equine Encephalitis (EEE)Common in North AmericaSpreads through Aedes and Culiseta spHumans are dead-end hosts but Aedes may spread from horse to human
Clinical symptoms similar to that of VEEHIGH MORTALITY in humans
Western Equine Encephalitis (WEE)Spreads through Culex and CulisetaCommon in rural areas of US in summer monthsFatality rate 3-4 death in 1-2 days Children have a 30 chance of CNS sequelae
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Pathophysiology of Equine EncephalitidesDefuse CNS involvementNeutrophils and macrophages infiltrate brain parenchyma causing focal necrosis and spottydemyelinationVascular inflammation with endothelial proliferation and small vessel thrombosis
EEELarge number of active virus entering in brain parenchymaEffects the perikaryon and dendrites of neurons with minimal glial cell infiltration
WEEDamage mediated by large number of immunologically active cells that enterbrainCell death by apoptosis primarily in the glial and inflammatory cells
FlaviviridaeBelongs to Baltimore class IVaPolyprotein is translated first which cleaves into many individual proteinsVirus buds inside cytoplasmic vesicles and the virus is released through
exocytosis
St Louis Encephalitis virus (SLE)Epidemiology
Transmitted by culex mosquitoesOvert infection depends upon
Efficiency of replication at extra neural sitesDegree of viremiaAge of the host
PathophysiologyVirus enters through BBB (astrocyte complex)
Or cross fenestrated endothelium (choroid plexus)Symptoms
Mortality 2-20 (higher in elderly)Malaise and fever only 20 develop sequelae (irritability memory loss movementdisorders motor deficits)Seizures and coma COMMONNo chronic illness
Japanese B Encephalitis virus (JBE)Epidemiology
Spread through Culex mosquitoesIncubation 4-14 days
Rural areas of AsiaSeptember 2010 India 319 deaths and Nepal 5 deaths
SymptomsViral prodrome- fever by 2nd weekEncephalitis syndrome with tremors NOT seizuresLow CSF IgGIgM ratio= higher death rate
West Nile Encephalitis virus (WNV)Epidemiology
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Wild birds are reservoir spreads through Aedes mosquitoes3-15 fatalVery RARE person to person transmission
SymptomsViral prodrome with maculopapular rash on trunk and extremitiesHeadache HIGH fever nuchal rigidity stupor tremor and seizures paralysis
BunyaviridaeAt least 200 different viruses included in this groupEnveloped viruses containing single-stranded negative polarity segmented (3) RNASpreads through mosquitoes ticks and flies
California Encephalitis virusLa Crosse virus
RhabdoviridaeLyssavirus RabiesStructure
Bullet shaped virusSingle-stranded negative polarity RNA
Helical nucleocapsid in an envelope5 proteins- NPMG and L
Surface glycoprotein attaches to cell receptors including Acetylcholine receptor atneuromuscular junctions
PathophysiologyViral entry into the cell is via endocytosisVirus has a preference for nerve and salivary gland cells (travels via axons to CNS)Spreads from brain to salivary glands kidneys and conjunctival cells (virus in tears )
EpidemiologyEstimated 35000-50000 cases worldwide
Highest in Asia ~90 casesEndozoonotic all warm blooded animals are susceptible
Urban- dogs and catsSylvatic- wildlife
SymptomsIncubation 20-90 days may extend to a yearNonspecific ndash general malaise fever headache (tingling pain and weakness at the bitsite)Progressive - neurologic symptoms including insomnia confusion slight or partialparalysis agitation hypersalivation dysphagia (hydrophobia)Paralytic ndashdisorientation stupor
Death within days after symptoms (~7 days)Diagnosis
Saliva- virus isolation RT-PCRSerum and CSF for rabies antibodies (FA and ELISA)Brain tissue- Negri bodies Babes nodules consisting of glial cells
TreatmentPrevention
Wash all wounds with soap and water
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1 dose of immune globulin and 4 doses of vaccine on days 137 amp14 days + 2boosters on days 0 and 3
New recommendations by CDC published on Mar 18 2010
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010(MMWR VOL59RR2 MAR 18 2010)
NOT PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent (eg povidine-iodinesolution) should be used to irrigate the wounds
Human rabies
immune globulin(HRIG)
Administer 20 IUkg body weight If anatomicallyfeasible the full dose should be infiltrated around and
into the wound(s) and any remaining volume shouldbe administered at an anatomical site (intramuscular
[IM]) distant from vaccine administration
Vaccine Human diploid cell vaccine (HDCV) or purified chickembryo cell vaccine (PCECV) 10 mL IM (deltoid but
never in the gluteal region) 1 each on days 0 3 7 and
14(For immunocompromised 5 shots)
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010
(MMWR VOL59RR2 MAR 18 2010)
PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent such as povidine-iodinesolution should be used to irrigate the wounds
HRIG HRIG should not be administered
Vaccine HDCV or PCECV 10 mL IM (deltoid but never in the
gluteal area) 1 each on days 0 and 3
For persons with immunosuppression rabies PEPshould be administered using all 5 doses of vaccine on
days 0 3 7 14 and 28
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Other virus infections of the CNSArenaviridae - Lymphocytic ChoriomeningitisTogaviridae- Rubella virusHerpesviridae - Human Herpes virus 1-8Retroviridae - HIV-1Other virus infections of the CNS
Papovaviridae - Polyoma virus (JC virus)-PML (Progressive Multifocal Leukoencephalopathy)Viral DNA in majority of healthy humansMultifocal signs including hemiparesis visual loss seizures dementia personalitychanges and gait problemsCharacteristic white matter lesions common in posterior occipital area
Paramyxoviridae - Mumps viruses and Measles- SSPE (Subacute Sclerosing Pan Encephalitis)Slow fatal condition after more than 10 years of measlesWorldwide more common in boys (31) than girlsBehavior changes in school age childrenFulminant course- 10 of cases death in 3 monthsChronic course- death in 4-10 years
Brain Abscess and EmpyemaLocalized bacterial infection of brain parenchyma and subdural or epidural spacesPressure from accumulation of exudates may permanently damage the brain tissueMay be fatal if not treated properlyAbscess
Fixed boundariesEmpyema
Lack of definable shape or sizeBrain Abscess
Symptoms
Usually are rapid and associated with their locationHeadacheChanges in mental status- drowsiness to comaGeneralized seizure
Fungal brain abscessDisseminated hematogenously from remote site ( lungs or oropharynx)Create multiple areas of infection within brainMeningoencephalitis occurs early by vascular invasionEtiology
Aspergillus Cryptococcus Candida
Transmissible Spongiform EncephalopathiesPrion is an abnormal isomer of normal host proteinNO NUCLEIC ACID presentReplicate without provoking antibody or inflammatory responseAre resistant to some inactivation methods used for bacteria and viruses (70 alcohol X-raysand UV light etc)Sensitive to autoclaving and bleachDisease confined to the CNS and may take decades to manifestCan be inherited (~15) of cases)
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PathogenesisNormal PrPc- glycoprotein with secondary structures dominated by Alpha helixPrion protein PrPSc- glycoprotein with secondary structures dominated by Beta-pleats When PrPSc molecules comes in contact with the normal PrPc molecule the normal PrPc changes into the abnormal PrPSc
Modified protein aggregates in neurons as myeloid plaques
Spongy appearance of cerebrum is due to the formation of vacuoles in the cortex andcerebellum
Spread of PrionsSporadic- no apparent causeInherited - through autosomal dominant traitIngestion - infected food cannibalism
Kuru-incubation ~20 yearsInvolves progressive trunchal shaking and unsteady gait Death within 3-24 months
Medical events- (Iatrogenic) through surgery organs etc
Creutzfeld Jekob Disease (CJD)Most common prion human diseasePeak incidence 55-65 years but can affect teenagersNo treatmentSymptoms
Insidious mental deteriorationEarly cerebellar and visual problemsSevere dementia in 6 monthsBrain and lower motor neuron involvementCases of CJD have been due to
Infected corneal transplantsReused improperly sterilized brain surgery equipment
Pituitary hormone injections derived from cadaversAccidental cuts during autopsies or surgeries
Bovine Variant of CJDBSE re-emerged in 1996 with progressive neurodegenerative disease resulting in patient deathNormally bovine but crossed to humans as Mad Cow DiseaseDiagnosis
Biopsy of BrainSpongiform encephalopathyAccumulation of abnormally folded protein
Sporadic diseaseCSF- no cells
CNS InfectionsThis was by no means a complete inventory of infectious agents involvedThere are many more however we discussed ONLY the very common and frequent infectionsThe original Mad Cow
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The Blood-Brain Barrier-including the endothelial cells lining the brain capillaries and are
cemented together by intracellular tight junctions-provide a barrier for micro-organisms and toxic
substances It also impedes the passage of the antibodies and antibiotics into the CSF resulting
in poor prognosis
Fenestratedendothelium
B-CSF-B
Thin Basement
Membrane
B-B-B B-CSF-B
Blood VesselICAMJunctions
Thick
BasementMembrane
Brain-CSF-B
Choroid plexus
epithelium
copyAQureshi S10
Comparison ofBlood-Brain Blood-CSF and Brain-CSF Barriers
Low antibody littl eno phagocytes and complement
B-B-B
CSFBrain
Gap Junctions
It is the entry and replication of the infectious agents that results in many different outcomes of
disease syndromes We will be studying only the very common and prominent infectious agentsand their role in the diseases of the CNS For these lectures we will focus the organisms that
are not covered in detail at other areas of this course The list of chapters and reading
references are only for your convenience to find the related information
Organ System approach in Medical Microbiology provides a framework and prospectiveThree organ systems are closed systemsBone and JointsVascularThe Central Nervous SystemInfections of these are associated with an increased morbidity and mortality
These systems are normally sterile and have no normal biota
Central Nervous System (CNS) InfectionsNo direct communication with the external environment (Blood Brain Barrier)Pathogens reach CNS either by direct extension from a contiguous structure or byhematogenous dissemination from a distant siteIn order to institute appropriate empiric therapy it is critical to know the normal biota and mostcommon pathogens associated with each of these distant sites
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TerminologyMeningitis- infection of the CNS coveringsEncephalitis- infection of brain parenchyma
Myelitis- infection of spinal cordMeningoencephalomyelitis - infection of many areas of brainAbscess- localized pockets of infection in spinal cord or brainEmpyema- epidural or subepidural abscess
Epidemiologic ConsiderationsPatient demographics- age immune statusDisease pattern- acute or chronicExposure history- exposure bites etcEpidemiology- geographic location season outbreaksEtiology of infection- bacterial viral fungal or protozoan
ENCEPHALITES OF VIRAL ETIOLOGY ENCEPHALITES OF VIRAL ETIOLOGY ENCEPHALITES OF VIRAL ETIOLOGY ENCEPHALITES OF VIRAL ETIOLOGY
Virus Geographic
Distribution
Age Group Predominant
Season
Herpes Virus 1amp2 All All None
West Nile Virus All Older adults Summer-Fall
EEE Virus Atlantic amp GulfCoast and Great
Lakes
Children Summer-Fall
WEE Virus Western US ampCanada
Infants amp Older adults Summer-Fall
California
Encephalitis Virus
Midwest amp NE US
S Canada
Older children Summer-Fall
Enteroviruses All Infants amp children Summer
Varicella-ZosterVirus
All Children ampImmunocompromised
Winter
Modified from Table 61-3 page 593 Schaecterrsquos Mechanisms of Microbial Diseases 4th Edition2007 A Qureshi S2010
Entry Replication and Spread
Hematogenous (Important for abscesses)
Meningococci from respiratory epitheliumWest Nile virus through insect biteRubella virus through Transplacental transmission
NeuralRabies peripheral nerves to nerve axons to ganglia and spinal cord to brainHuman Herpes viruses 1-3 through nerves
Direct inoculation through trauma or injuryPenetrating head trauma and surgery
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Most common- Staph aureusImmunodeficient or HIV infections- Nocardia Aspergillus Candida
Most likely through Choroid plexus as it is highly vascularized inflammation may increase entryinto CNSDirect extension
Infections of teeth middle ear or mastoids or sinuses
Most common etiologyAerobic and anaerobic streptococciBacteroidesEnterobacteriaceaePsudomadsFusibacteriumPeptococcus
Etiology depends upon location of the source of infectionMouth- mixed biotaLungs- Streptococci Fusibaterium Corynebacterium Peptococcus spHeart- Strep viridans Staph aureusUrinary tract- Enterobacteriaceae Pseudomonas
Wounds- Staph aureus
CNS SyndromesMeningitis
Acute Meningitis- viral or bacterialChronic Meningitis- fungi and tubercle bacilli
Encephalitis- viralMyelitis- viralBrain Abscesses
Acute Brain Abscess- generally poly microbialChronic Brain Abscess- tubercle bacilli fungi and protozoa
MeningitisInfection of the membranes and fluid surrounding the brain and spinal cord (spinalmeningitis) causing inflammation of the meninges
MeningismGroup of Symptoms and signs associated with the inflammation
HeadacheNuchal rigidityNausea and vomitingPhotophobia
Tests for MeningismDemonstrate inability to flex the neck and touch the chin to the chest
Demonstrate inability to oppose the nose with the kneesTripod sign- inability to sit without making a tripod with handsKernigrsquos sign- patientrsquos leg can not be straightened because of hamstring spasmBrudzinskirsquos neck sign- patient retracts the legs when neck is liftedSymptoms associated with MeningitisDepend upon age microorganism and the route to meninges
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Early symptoms (nonspecific)FeverMalaiseAches and painsNauseaVomiting
Headache
HALL MARKS of Meningitis
Symptoms associated with MeningitisDiagnosis of CNS infectionsCerebrospinal Fluid
Chemical and cellular analysisCulturePCR
FEATURES OF CSF
Etiology Leukocytes
(mm3)
Neutrophils
Glucose
(mgdL)
Protein
(mgdL)
Normal 0-6 0 40-80 20-50
Meningitis
Acute Bacterial
gt1000 gt50 0-10 gt100
Viral 10-1000Usually lt300
High for 24hrs then lt50
40-80 50-100
Chronic Mycobact
amp Fungal
100-500 lt10 le40 gt100
(Mycobact)
50-100
(Fungal)
Encephalitis Viral 10-500 High for 24
hrs then lt50
40-80 50-100
BrainAbscess
Bacterial
Fungal
10-100 lt50 40-80 50-100
10-500 RBCs in HHV-1 Infection A Qureshi S2010
Neuroimaging
Helpful in partial differentiation of viral encephalitisJapanese B virus grey matter involvementNipah virus multiple small white matter lesionsHuman herpes virus-1 hemorrhagesAbscesses and Empyema differentiation
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MeningitisInflammation of the meninges occurs due to viral or bacterial infectionsAseptic
Over 50 of the cases are due to a variety of virusesRest of the cases are due to bacteria with special growth requirements or slow growers
CAUSES OF ASEPTIC ASEPTIC ASEPTIC ASEPTIC MENINGITIS
Viruses Bacteria
Common Enteroviruses
Arboviruses
HHV-2
Borrelia burgdorferi
Inadequately treated bacterial
meningitis
Uncommon Mumps
HHV-5 (CMV)
HHV-6
HIV
Mycobacterium tuberculosis
Leptospira sp
Micoplasma pneumoniae
Incidence varies with the region
Modified from Neurol Clin 2008 26635
A Qureshi S10
Viral Infections of CNS
Viruses use at least two pathways to enter the CNSHematogenous (most common)Neural
Through Olfatory nerve- HHV-1amp2Intra-axonal through neuron route- Rabies
Direct injuryViral infections range from meningitis to myelitis
Viral Meningitis Common causes of Aseptic meningitis
Enteroviruses ( ECHO) coxsackie and poliovirusHerpes virus and other viruses are less common
Mumps virus meningitis is a complication of infectionCSF findings
Glucose ndashnormalProtein- moderately highWBC count- increased predominantly lymphocytes
Gram stain- NO BACTERIA
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EnterovirusesEnteroviruses belong to family PicornavirideaNaked small (25-30 nm) icoshedral virusesResistant to pH 3-9 detergents and heatContain single-stranded positive polarity RNA
Transfecting viruses
Baltimore Class IVa RNA replication in cytoplasmMost viruses are CytolyticOver 63 serotypes involved in meningitisPoliovirus has only 3 serotypes and may cause meningitis to myelitisEradicated from the Western Hemisphere through OPV
More than 90 of viral meningitis cases are due to EnterovirusesOther syndromes caused by enteroviruses include
Hand-foot and mouth diseaseHerpanginaMyocarditisPleurodynia
Acute hemorrhagic conjunctivitis
Clinical syndromes are determined byVirus class and serotypeTissue tropismInfectious dosePortal of entryPatient age sex Immune competence
EpidemiologyWorldwide distributionHumans are the only reservoir
Asymptomatic infections are commonShow seasonality
Temperate climates- Summer to Fall (water)Tropical climates- year-round (fecal-oral)Infants and children MOST susceptible
Please refer to Murray et al (6 th Ed)Box 56-4 p 556
PoliovirusesMember of family PicornaviridaeSame viral characters as that of EnterovirusesSpreads through fecal-oral route by consuming contaminated food and waterThrough direct contact with infected stool or throat secretions
Symptoms common to those of meningeal irritationHeadache fever nuchal rigidity followed by weakness in one or more extremities
Clinical syndromeAcute Flaccid Paralysis due to infection of anterior horn of grey matter
PathogenesisInfects enterocytes of the GI tractTransverses intestinal wall through basement membrane
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Moves into gut-associated lymphoid tissue eg Peyerrsquos patches (site of primaryreplication)Resulting viremia seeds peripheral tissue virus enters the neurons of the peripheralnervous system that innervates the peripheral tissues and the virus traffics to the CNSusing retrograde axonal transport
(Lancaster and Pfeiffer 2010)
Outcomes of infectionInapparent infections
95 asymptomatic virus in RESDiagnosis by virus isolation from feces and oropharynx and by specific serumantibodies
Abortive polio (minor illness)- flu like symptomsSimilar to any systemic viral infection
Polio encephalitis- RARENon-paralytic polio (aseptic meningitis)
Similar to other enteroviral meningitis
Paralytic polio (lt2 of cases)Viral spread is normally restricted due to
Limited replication of virus in peripheral neuronsInsufficient retrograde axonal transport in peripheral neuronsInnate resistance through IFN α β production
When these barriers are breeched the out come will be paralytic polioSpinal - flaccid paralysis due lysis of the anterior horn cellsBulbar - paralysis of cranial nerve IX and X medullarrespiratory centers
PreventionInactivated vaccine
Formalized Salk vaccine injected im
Local antibody is not producedMostly used in Western Hemisphere (where polio is considered eradicated)
Please see Table 56-2 in Murray et al 6 th Ed p 561 Live oral vaccine
Sabin vaccine is stable at room temperature with MgCl2Produces secretory antibodiesVirus can spread to contacts and enhance herd immunity and may causeparalytic polio (~1 in 4 million)
Please see Table 56-2 in Murray et al 6 th Ed p 561
Meningitis (Continued)
Septic (as opposed to viral Aseptic) Caused by bacteria onlyAssociated with high Mortality and SeverityEtiology is AGE dependent
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CAUSES OF SEPTIC SEPTIC SEPTIC SEPTIC MENINGITIS
AGE Most common Others
Birth to 3 months Streptococcus agalactiae Escherichia coli L monocytogenes
3 to 60 months Streptococcuspneumoniae
Neisseria meningitidis
H influenzae type b
gt 60 months Streptococcuspneumoniae
Neisseria meningitidis
L monocytogenes
Other Gram negative
organisms
Any age (cranial
surgery)
Staphylococcus aureus
Any age
(immunosuppressed)
L monocytogenes
Other Gram negatives
(including P aeroginosa)
Bacterial Infections of CNSOver 25 infectious agents involvedSevere life threatening infections requiring prompt diagnosis and treatmentSeptic meningitis (Bacterial meningitis)Bacterial invasion into CNS
Invasion from nearby siteMiddle ear or chronic sinusitis
Spread from a distant siteHematogenous invasion
Direct introductionRARE sometimes the source cannot be identified
Bacterial MeningitisNeonates- Strep agalactiae Coliforms and Listeria monocytogenesInfants- Streptococcus pneumoniae Neisseria meningitidis and H influenzaeChildren- Strep pneumoniae N meningitidis and Listeria monocytogenes Streptococcus pneumoniae most common except neonatesMore than 75 of total cases are caused by N meningitidis Strep pneumoniae and Hinfluenzae combined
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CAUSES OF SEPTIC SEPTIC SEPTIC SEPTIC MENINGITIS
AGE Most common Others
Birth to 3 months Streptococcus agalactiae Escherichia coli L monocytogenes
3 to 60 months Streptococcuspneumoniae
Neisseria meningitidis
H influenzae type b
gt 60 months Streptococcuspneumoniae
Neisseria meningitidis
L monocytogenes
Other Gram negative
organisms
Any age (cranial
surgery)
Staphylococcus aureus
Any age
(immunosuppressed)
L monocytogenes
Other Gram negatives
(including P aeroginosa)
Bacterial Virulence FactorsNeisseria meningitidis
Capsule IgA protease pili and endotoxinHaemophilus influenzae
Capsule IgA protease pili and endotoxin Streptococcus pneumoniae
Capsule and IgA protease only
Neisseria meningitidisGram negative coffee bean shaped intracellular (PMNs) exclusively human pathogenMany members of the genus are commensals of upper respiratory tractAbout 30 of the population may transiently carry N meningitidis Responsible for more than 75 cases of septic meningitis ( Reported by Dr Jungkind) Transmission is via droplet inhalationMore than 13 of the cases occur in the first five years of ageHigh morbidity and mortality ~50 survivors have neurologic or other sequelae
DiagnosisClinical signs- rash (Tumbler test) sepsis fever nuchal rigidityCSF tap- protein glucose and WBC count
Culture- fastidious organism requires 5-10 CO2
Blood or CSF sample- plate on chocolate agarNasopharyngeal swab- plate on to Modified Martin-Thayer agar
Contains antibiotics to inhibit normal biotaRapid techniques
Latex agglutinationPCR
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PreventionTetravalent vaccine composed of Groups A C Y and W135 (Group B is weaklyimmunogenic)
Protection is group specificProtection is limited to ~3 yearsVaccination does not protect from carriage of the organism
Vaccine is poorly immunogenic for infants under 2 years of age
Streptococcus agalactiae Beta hemolytic Taxos A resistant Group B streptococcusNormal female genital organism (~40 colonized))60 mortality for babies who develop meningitis during the first week of life
Premature birth is an important risk factorNeonates
Lethargy fever sepsis and respiratory distressChildren and adults
Puerperal fever at delivery and other skin and soft tissue infections
Streptococcus pneumoniaeGram positive lancet shaped alpha hemolytic Taxos P sensitive cocci (Optochin)Part of normal flora of 20 adults and gt75 healthy childrenMOST COMMON cause of bacterial meningitisHighest cause of infantile meningitisMortality rate for pneumococcal meningitis is ~25Neurological sequelae is ~50
In elderly it may follow pneumoniaMiddle ear infectionsSinusiPathogenesis (Braun et al2002 J Clin Invest 10919-27)
Pathogenesis
Hydrogen peroxide- due to absence of catalase large amounts accumulate and enhanceapoptosisPneumolysin
pore forming toxinPotent neurotoxin can trigger cellular apoptosis
Pathogenesis (Guikel et al2003 PNAS10014363-14367)In mouse models invasion can occur through nasopharynx (not hematogenous)Teichoic and lipoteichoic acids of cell wall mediate binding to the gangliosides expressedon the neuronsSubsequent travel is then via retrograde axonal transport along olfactory neurons
Haemophilus influenzae
Gram negative fastidious encapsulated pleomorphic organismsSpread via blood from respiratory tract to the brainInfection opportunity between 4 months to 3 yearsGreater risk of permanent neurologic damage than any other bacterial meningitisVaccines made with type B capsular polysaccharide
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Enterobacteriaceae
Escherichia coli K1Gram negative facultative anaerobesDuring pregnancy increased colonization of K1 strain with 8 mortality
Spreads from nasopharynx to the meningesEnterobacteriaceae Symptoms
lt1 month old- irritability lethargy vomiting lack of appetite and seizures4-18 months- nuchal rigidity tense fontanels and feverOlder children amp adults- headache vomiting confusion lethargy seizures and feve
Interactions during meningitis
Escherichia coli GI respiratory orgenitourinary tract
bloodstream
Slide kindly provided by Dr J Rayner
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Klebsiella pneumoniaeGram negative rodsHigh incidence in cockroach infested areasEarly onset- lt3 days- 2nd only to GBS
(leukopenia and neutropenia)Late onset- 8-28 days-2nd only to Staphylococcus
(leukocytosis and neutrophilia)Symptoms
Lethargy poor feeding little cry fever scleremaCulture from blood CSF urineC-reactive protein positive
Listeria monocytogenesGram positive non spore forming aerobic motile rodsEpidemiology
Food-borne (dairy and deli)Soil water decaying vegetation
Human intestines may be reservoir
2-12 humans carry the organismCan be transmitted to the baby during delivery (may cause spontaneous abortions)Pathogenesis
Grows in macrophagesReleases ldquoInternalinrdquo- as a cell attachment molecule trigger entryListeriolysin- protein that helps in movement within the cellHemolysin- pore-forming toxin Allows escape from phagosome to the phagosoleUses host cell actin to move to the new cells
DiagnosisIntracellular gram positive rods in macrophages and neutrophilsCSF culture- looks like β-Strep but catalase + and ldquotumblerdquo
Slide is kindly provided by Dr Rayner
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Spirochetes Infections of CNSTreponema pallidum
Early stages are infectious and no CNS involvementTakes about 10 year or longer for non treated cases
Neurosyphilis is the Tertiary stage of the disease and no longer infectiousDelayed hypersensitivity is part of the pathologic mechanism of tissue damageCommonly found in different tissues of the body as ldquoGummasrdquoInfection of CNS is via meningovascular routeSpirochetes Infections of CNSSymptoms
CNS degenerative changes resulting in mental changesMay have frank psychosisShuffling gait ldquotabes dorsalisrdquo
DiagnosisSpinal fluid may be helpfulElevated WBCs and protein
VDRL positive
Leptospira interogans Animals are reservoirsSpreads through animal urine contaminated water and food (survives weeks in water)No body of water in the US is free from itSensitive to Acid pH drying and soap~100 casesyearSewer workers miners veterinarians and meat packers are at risk Spirochetes Infections of CNSSymptoms
Incubation 7-13 days (range 5 days - 4 weeks)
Bacteremic phase- influenza like symptoms and fever (bacteria NOW enter the CNS)2 nd Phase - ~3+weeksHeadache with ldquoasepticrdquo meningitisSometimes hemodynamic collapse
DiagnosisBlood cultureCSF analysis and cultureRise in antibody between acute and convalescent stages
Borrelia burgdorferi~15 Neurologic abnormalities rarely fatal
Starts with a tick biteLarge spirochetes- 02x10-30 micromSpirochetes Infections of CNS
SymptomsClassic ldquobullrsquos eyerdquo rash fever joint pain meningeal irritation2nd Stage- dissemination system wide3rd Stage- mild neurologic or frank encephalitis
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DiagnosisLoose irregular spirals Silver or immunoflourescent stainDifficult to cultureCDC recommends antibody screen using ELISA
Fungal Infections of CNSDisseminate hematogenously from a remote site of infection (oropharynx or lung)Create multiple areas of infection within brain and other organsCan cause abscessesMeningoencephalitis occurs early by vascular invasion by fungusCan see secondary thrombosis cerebral infarction and hemorrhages
Common fungiCandida albicansCryptococcus neoformansHistoplasma capsulatumAspergillus fumigatus
DiagnosisAntibody studiesCXRCandida- forms granulomatus reaction Yeast forms seen with silver stainCryptococcus- fungi appear like encapsulated spheres Capsules can be seen bymucicarmine stain Histoplasma- CT scan Aspergillus- branching hyphae classical appearance
Please revisit your notes on Respiratory fungal infections by Dr Lennon
Encephalitis
EtiologyViral
Herpes viruses enteroviruses arboviruses rabies virus HIV HTLV-1Paramyxoviruses (mumps rubeola virus and arenaviruses)
Bacterial (RARE)Exceptions Legionella pneumoniae Borrelia burgdorferi Treponema pallidum
FungalCryptococcus neoformans
ParasiticPlasmodium falciparum Trypanosomes
MyelitisAcute inflammation of the spinal cord
Depending upon virus this can lead to flaccid paralysisSymptoms
HeadacheFeverIrritation followed by
Weakness of one or more extremitiesEtiology
Poliovirus was the leading cause before vaccinationWest Nile virus is the most significant after 2000
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Defined as inflammation of brain parenchymaEncephalitis is considered clinically a more severe syndrome than viral meningitisSymptoms
HeadacheFever
Altered consciousness-lethargy to confusion and comaBehavioral and speech disturbanceSeizures
Arboviruses Arthropod-borne viral infectionsDistributed worldwideTransmitted by mosquitoes and ticksSporadic and epidemic encephalitisSeizures are generally the complications in children
All arboviruses are enveloped viruses with icosahedral nucleocapsid and contain a transfecting RNA
Major families of arboviruses (Togaviridae and Flaviviridae )Togaviridae
Belongs to Baltimore Class IVbEarly and late proteins madeVirus buds at the plasma membrane
TogaviridaeVenezuelan Equine Encephalitis (VEE)Togaviridae (alphavirus)
Spread through Culex and Aedes mosquitoesSymptoms
Prodrome- fever chills weakness headache myalgia (due to viral replication )Rapid progression- nuchal rigidity confusion somnolence seizure in 50 of cases andcoma (due to spread through microvascular permeability of brain then cell-to-celloccurs via axon and dendrites )NO DEATHS in humans 80 mortality in horses
Eastern Equine Encephalitis (EEE)Common in North AmericaSpreads through Aedes and Culiseta spHumans are dead-end hosts but Aedes may spread from horse to human
Clinical symptoms similar to that of VEEHIGH MORTALITY in humans
Western Equine Encephalitis (WEE)Spreads through Culex and CulisetaCommon in rural areas of US in summer monthsFatality rate 3-4 death in 1-2 days Children have a 30 chance of CNS sequelae
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Pathophysiology of Equine EncephalitidesDefuse CNS involvementNeutrophils and macrophages infiltrate brain parenchyma causing focal necrosis and spottydemyelinationVascular inflammation with endothelial proliferation and small vessel thrombosis
EEELarge number of active virus entering in brain parenchymaEffects the perikaryon and dendrites of neurons with minimal glial cell infiltration
WEEDamage mediated by large number of immunologically active cells that enterbrainCell death by apoptosis primarily in the glial and inflammatory cells
FlaviviridaeBelongs to Baltimore class IVaPolyprotein is translated first which cleaves into many individual proteinsVirus buds inside cytoplasmic vesicles and the virus is released through
exocytosis
St Louis Encephalitis virus (SLE)Epidemiology
Transmitted by culex mosquitoesOvert infection depends upon
Efficiency of replication at extra neural sitesDegree of viremiaAge of the host
PathophysiologyVirus enters through BBB (astrocyte complex)
Or cross fenestrated endothelium (choroid plexus)Symptoms
Mortality 2-20 (higher in elderly)Malaise and fever only 20 develop sequelae (irritability memory loss movementdisorders motor deficits)Seizures and coma COMMONNo chronic illness
Japanese B Encephalitis virus (JBE)Epidemiology
Spread through Culex mosquitoesIncubation 4-14 days
Rural areas of AsiaSeptember 2010 India 319 deaths and Nepal 5 deaths
SymptomsViral prodrome- fever by 2nd weekEncephalitis syndrome with tremors NOT seizuresLow CSF IgGIgM ratio= higher death rate
West Nile Encephalitis virus (WNV)Epidemiology
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Wild birds are reservoir spreads through Aedes mosquitoes3-15 fatalVery RARE person to person transmission
SymptomsViral prodrome with maculopapular rash on trunk and extremitiesHeadache HIGH fever nuchal rigidity stupor tremor and seizures paralysis
BunyaviridaeAt least 200 different viruses included in this groupEnveloped viruses containing single-stranded negative polarity segmented (3) RNASpreads through mosquitoes ticks and flies
California Encephalitis virusLa Crosse virus
RhabdoviridaeLyssavirus RabiesStructure
Bullet shaped virusSingle-stranded negative polarity RNA
Helical nucleocapsid in an envelope5 proteins- NPMG and L
Surface glycoprotein attaches to cell receptors including Acetylcholine receptor atneuromuscular junctions
PathophysiologyViral entry into the cell is via endocytosisVirus has a preference for nerve and salivary gland cells (travels via axons to CNS)Spreads from brain to salivary glands kidneys and conjunctival cells (virus in tears )
EpidemiologyEstimated 35000-50000 cases worldwide
Highest in Asia ~90 casesEndozoonotic all warm blooded animals are susceptible
Urban- dogs and catsSylvatic- wildlife
SymptomsIncubation 20-90 days may extend to a yearNonspecific ndash general malaise fever headache (tingling pain and weakness at the bitsite)Progressive - neurologic symptoms including insomnia confusion slight or partialparalysis agitation hypersalivation dysphagia (hydrophobia)Paralytic ndashdisorientation stupor
Death within days after symptoms (~7 days)Diagnosis
Saliva- virus isolation RT-PCRSerum and CSF for rabies antibodies (FA and ELISA)Brain tissue- Negri bodies Babes nodules consisting of glial cells
TreatmentPrevention
Wash all wounds with soap and water
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1 dose of immune globulin and 4 doses of vaccine on days 137 amp14 days + 2boosters on days 0 and 3
New recommendations by CDC published on Mar 18 2010
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010(MMWR VOL59RR2 MAR 18 2010)
NOT PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent (eg povidine-iodinesolution) should be used to irrigate the wounds
Human rabies
immune globulin(HRIG)
Administer 20 IUkg body weight If anatomicallyfeasible the full dose should be infiltrated around and
into the wound(s) and any remaining volume shouldbe administered at an anatomical site (intramuscular
[IM]) distant from vaccine administration
Vaccine Human diploid cell vaccine (HDCV) or purified chickembryo cell vaccine (PCECV) 10 mL IM (deltoid but
never in the gluteal region) 1 each on days 0 3 7 and
14(For immunocompromised 5 shots)
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010
(MMWR VOL59RR2 MAR 18 2010)
PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent such as povidine-iodinesolution should be used to irrigate the wounds
HRIG HRIG should not be administered
Vaccine HDCV or PCECV 10 mL IM (deltoid but never in the
gluteal area) 1 each on days 0 and 3
For persons with immunosuppression rabies PEPshould be administered using all 5 doses of vaccine on
days 0 3 7 14 and 28
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Other virus infections of the CNSArenaviridae - Lymphocytic ChoriomeningitisTogaviridae- Rubella virusHerpesviridae - Human Herpes virus 1-8Retroviridae - HIV-1Other virus infections of the CNS
Papovaviridae - Polyoma virus (JC virus)-PML (Progressive Multifocal Leukoencephalopathy)Viral DNA in majority of healthy humansMultifocal signs including hemiparesis visual loss seizures dementia personalitychanges and gait problemsCharacteristic white matter lesions common in posterior occipital area
Paramyxoviridae - Mumps viruses and Measles- SSPE (Subacute Sclerosing Pan Encephalitis)Slow fatal condition after more than 10 years of measlesWorldwide more common in boys (31) than girlsBehavior changes in school age childrenFulminant course- 10 of cases death in 3 monthsChronic course- death in 4-10 years
Brain Abscess and EmpyemaLocalized bacterial infection of brain parenchyma and subdural or epidural spacesPressure from accumulation of exudates may permanently damage the brain tissueMay be fatal if not treated properlyAbscess
Fixed boundariesEmpyema
Lack of definable shape or sizeBrain Abscess
Symptoms
Usually are rapid and associated with their locationHeadacheChanges in mental status- drowsiness to comaGeneralized seizure
Fungal brain abscessDisseminated hematogenously from remote site ( lungs or oropharynx)Create multiple areas of infection within brainMeningoencephalitis occurs early by vascular invasionEtiology
Aspergillus Cryptococcus Candida
Transmissible Spongiform EncephalopathiesPrion is an abnormal isomer of normal host proteinNO NUCLEIC ACID presentReplicate without provoking antibody or inflammatory responseAre resistant to some inactivation methods used for bacteria and viruses (70 alcohol X-raysand UV light etc)Sensitive to autoclaving and bleachDisease confined to the CNS and may take decades to manifestCan be inherited (~15) of cases)
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PathogenesisNormal PrPc- glycoprotein with secondary structures dominated by Alpha helixPrion protein PrPSc- glycoprotein with secondary structures dominated by Beta-pleats When PrPSc molecules comes in contact with the normal PrPc molecule the normal PrPc changes into the abnormal PrPSc
Modified protein aggregates in neurons as myeloid plaques
Spongy appearance of cerebrum is due to the formation of vacuoles in the cortex andcerebellum
Spread of PrionsSporadic- no apparent causeInherited - through autosomal dominant traitIngestion - infected food cannibalism
Kuru-incubation ~20 yearsInvolves progressive trunchal shaking and unsteady gait Death within 3-24 months
Medical events- (Iatrogenic) through surgery organs etc
Creutzfeld Jekob Disease (CJD)Most common prion human diseasePeak incidence 55-65 years but can affect teenagersNo treatmentSymptoms
Insidious mental deteriorationEarly cerebellar and visual problemsSevere dementia in 6 monthsBrain and lower motor neuron involvementCases of CJD have been due to
Infected corneal transplantsReused improperly sterilized brain surgery equipment
Pituitary hormone injections derived from cadaversAccidental cuts during autopsies or surgeries
Bovine Variant of CJDBSE re-emerged in 1996 with progressive neurodegenerative disease resulting in patient deathNormally bovine but crossed to humans as Mad Cow DiseaseDiagnosis
Biopsy of BrainSpongiform encephalopathyAccumulation of abnormally folded protein
Sporadic diseaseCSF- no cells
CNS InfectionsThis was by no means a complete inventory of infectious agents involvedThere are many more however we discussed ONLY the very common and frequent infectionsThe original Mad Cow
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TerminologyMeningitis- infection of the CNS coveringsEncephalitis- infection of brain parenchyma
Myelitis- infection of spinal cordMeningoencephalomyelitis - infection of many areas of brainAbscess- localized pockets of infection in spinal cord or brainEmpyema- epidural or subepidural abscess
Epidemiologic ConsiderationsPatient demographics- age immune statusDisease pattern- acute or chronicExposure history- exposure bites etcEpidemiology- geographic location season outbreaksEtiology of infection- bacterial viral fungal or protozoan
ENCEPHALITES OF VIRAL ETIOLOGY ENCEPHALITES OF VIRAL ETIOLOGY ENCEPHALITES OF VIRAL ETIOLOGY ENCEPHALITES OF VIRAL ETIOLOGY
Virus Geographic
Distribution
Age Group Predominant
Season
Herpes Virus 1amp2 All All None
West Nile Virus All Older adults Summer-Fall
EEE Virus Atlantic amp GulfCoast and Great
Lakes
Children Summer-Fall
WEE Virus Western US ampCanada
Infants amp Older adults Summer-Fall
California
Encephalitis Virus
Midwest amp NE US
S Canada
Older children Summer-Fall
Enteroviruses All Infants amp children Summer
Varicella-ZosterVirus
All Children ampImmunocompromised
Winter
Modified from Table 61-3 page 593 Schaecterrsquos Mechanisms of Microbial Diseases 4th Edition2007 A Qureshi S2010
Entry Replication and Spread
Hematogenous (Important for abscesses)
Meningococci from respiratory epitheliumWest Nile virus through insect biteRubella virus through Transplacental transmission
NeuralRabies peripheral nerves to nerve axons to ganglia and spinal cord to brainHuman Herpes viruses 1-3 through nerves
Direct inoculation through trauma or injuryPenetrating head trauma and surgery
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Most common- Staph aureusImmunodeficient or HIV infections- Nocardia Aspergillus Candida
Most likely through Choroid plexus as it is highly vascularized inflammation may increase entryinto CNSDirect extension
Infections of teeth middle ear or mastoids or sinuses
Most common etiologyAerobic and anaerobic streptococciBacteroidesEnterobacteriaceaePsudomadsFusibacteriumPeptococcus
Etiology depends upon location of the source of infectionMouth- mixed biotaLungs- Streptococci Fusibaterium Corynebacterium Peptococcus spHeart- Strep viridans Staph aureusUrinary tract- Enterobacteriaceae Pseudomonas
Wounds- Staph aureus
CNS SyndromesMeningitis
Acute Meningitis- viral or bacterialChronic Meningitis- fungi and tubercle bacilli
Encephalitis- viralMyelitis- viralBrain Abscesses
Acute Brain Abscess- generally poly microbialChronic Brain Abscess- tubercle bacilli fungi and protozoa
MeningitisInfection of the membranes and fluid surrounding the brain and spinal cord (spinalmeningitis) causing inflammation of the meninges
MeningismGroup of Symptoms and signs associated with the inflammation
HeadacheNuchal rigidityNausea and vomitingPhotophobia
Tests for MeningismDemonstrate inability to flex the neck and touch the chin to the chest
Demonstrate inability to oppose the nose with the kneesTripod sign- inability to sit without making a tripod with handsKernigrsquos sign- patientrsquos leg can not be straightened because of hamstring spasmBrudzinskirsquos neck sign- patient retracts the legs when neck is liftedSymptoms associated with MeningitisDepend upon age microorganism and the route to meninges
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Early symptoms (nonspecific)FeverMalaiseAches and painsNauseaVomiting
Headache
HALL MARKS of Meningitis
Symptoms associated with MeningitisDiagnosis of CNS infectionsCerebrospinal Fluid
Chemical and cellular analysisCulturePCR
FEATURES OF CSF
Etiology Leukocytes
(mm3)
Neutrophils
Glucose
(mgdL)
Protein
(mgdL)
Normal 0-6 0 40-80 20-50
Meningitis
Acute Bacterial
gt1000 gt50 0-10 gt100
Viral 10-1000Usually lt300
High for 24hrs then lt50
40-80 50-100
Chronic Mycobact
amp Fungal
100-500 lt10 le40 gt100
(Mycobact)
50-100
(Fungal)
Encephalitis Viral 10-500 High for 24
hrs then lt50
40-80 50-100
BrainAbscess
Bacterial
Fungal
10-100 lt50 40-80 50-100
10-500 RBCs in HHV-1 Infection A Qureshi S2010
Neuroimaging
Helpful in partial differentiation of viral encephalitisJapanese B virus grey matter involvementNipah virus multiple small white matter lesionsHuman herpes virus-1 hemorrhagesAbscesses and Empyema differentiation
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MeningitisInflammation of the meninges occurs due to viral or bacterial infectionsAseptic
Over 50 of the cases are due to a variety of virusesRest of the cases are due to bacteria with special growth requirements or slow growers
CAUSES OF ASEPTIC ASEPTIC ASEPTIC ASEPTIC MENINGITIS
Viruses Bacteria
Common Enteroviruses
Arboviruses
HHV-2
Borrelia burgdorferi
Inadequately treated bacterial
meningitis
Uncommon Mumps
HHV-5 (CMV)
HHV-6
HIV
Mycobacterium tuberculosis
Leptospira sp
Micoplasma pneumoniae
Incidence varies with the region
Modified from Neurol Clin 2008 26635
A Qureshi S10
Viral Infections of CNS
Viruses use at least two pathways to enter the CNSHematogenous (most common)Neural
Through Olfatory nerve- HHV-1amp2Intra-axonal through neuron route- Rabies
Direct injuryViral infections range from meningitis to myelitis
Viral Meningitis Common causes of Aseptic meningitis
Enteroviruses ( ECHO) coxsackie and poliovirusHerpes virus and other viruses are less common
Mumps virus meningitis is a complication of infectionCSF findings
Glucose ndashnormalProtein- moderately highWBC count- increased predominantly lymphocytes
Gram stain- NO BACTERIA
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EnterovirusesEnteroviruses belong to family PicornavirideaNaked small (25-30 nm) icoshedral virusesResistant to pH 3-9 detergents and heatContain single-stranded positive polarity RNA
Transfecting viruses
Baltimore Class IVa RNA replication in cytoplasmMost viruses are CytolyticOver 63 serotypes involved in meningitisPoliovirus has only 3 serotypes and may cause meningitis to myelitisEradicated from the Western Hemisphere through OPV
More than 90 of viral meningitis cases are due to EnterovirusesOther syndromes caused by enteroviruses include
Hand-foot and mouth diseaseHerpanginaMyocarditisPleurodynia
Acute hemorrhagic conjunctivitis
Clinical syndromes are determined byVirus class and serotypeTissue tropismInfectious dosePortal of entryPatient age sex Immune competence
EpidemiologyWorldwide distributionHumans are the only reservoir
Asymptomatic infections are commonShow seasonality
Temperate climates- Summer to Fall (water)Tropical climates- year-round (fecal-oral)Infants and children MOST susceptible
Please refer to Murray et al (6 th Ed)Box 56-4 p 556
PoliovirusesMember of family PicornaviridaeSame viral characters as that of EnterovirusesSpreads through fecal-oral route by consuming contaminated food and waterThrough direct contact with infected stool or throat secretions
Symptoms common to those of meningeal irritationHeadache fever nuchal rigidity followed by weakness in one or more extremities
Clinical syndromeAcute Flaccid Paralysis due to infection of anterior horn of grey matter
PathogenesisInfects enterocytes of the GI tractTransverses intestinal wall through basement membrane
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Moves into gut-associated lymphoid tissue eg Peyerrsquos patches (site of primaryreplication)Resulting viremia seeds peripheral tissue virus enters the neurons of the peripheralnervous system that innervates the peripheral tissues and the virus traffics to the CNSusing retrograde axonal transport
(Lancaster and Pfeiffer 2010)
Outcomes of infectionInapparent infections
95 asymptomatic virus in RESDiagnosis by virus isolation from feces and oropharynx and by specific serumantibodies
Abortive polio (minor illness)- flu like symptomsSimilar to any systemic viral infection
Polio encephalitis- RARENon-paralytic polio (aseptic meningitis)
Similar to other enteroviral meningitis
Paralytic polio (lt2 of cases)Viral spread is normally restricted due to
Limited replication of virus in peripheral neuronsInsufficient retrograde axonal transport in peripheral neuronsInnate resistance through IFN α β production
When these barriers are breeched the out come will be paralytic polioSpinal - flaccid paralysis due lysis of the anterior horn cellsBulbar - paralysis of cranial nerve IX and X medullarrespiratory centers
PreventionInactivated vaccine
Formalized Salk vaccine injected im
Local antibody is not producedMostly used in Western Hemisphere (where polio is considered eradicated)
Please see Table 56-2 in Murray et al 6 th Ed p 561 Live oral vaccine
Sabin vaccine is stable at room temperature with MgCl2Produces secretory antibodiesVirus can spread to contacts and enhance herd immunity and may causeparalytic polio (~1 in 4 million)
Please see Table 56-2 in Murray et al 6 th Ed p 561
Meningitis (Continued)
Septic (as opposed to viral Aseptic) Caused by bacteria onlyAssociated with high Mortality and SeverityEtiology is AGE dependent
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CAUSES OF SEPTIC SEPTIC SEPTIC SEPTIC MENINGITIS
AGE Most common Others
Birth to 3 months Streptococcus agalactiae Escherichia coli L monocytogenes
3 to 60 months Streptococcuspneumoniae
Neisseria meningitidis
H influenzae type b
gt 60 months Streptococcuspneumoniae
Neisseria meningitidis
L monocytogenes
Other Gram negative
organisms
Any age (cranial
surgery)
Staphylococcus aureus
Any age
(immunosuppressed)
L monocytogenes
Other Gram negatives
(including P aeroginosa)
Bacterial Infections of CNSOver 25 infectious agents involvedSevere life threatening infections requiring prompt diagnosis and treatmentSeptic meningitis (Bacterial meningitis)Bacterial invasion into CNS
Invasion from nearby siteMiddle ear or chronic sinusitis
Spread from a distant siteHematogenous invasion
Direct introductionRARE sometimes the source cannot be identified
Bacterial MeningitisNeonates- Strep agalactiae Coliforms and Listeria monocytogenesInfants- Streptococcus pneumoniae Neisseria meningitidis and H influenzaeChildren- Strep pneumoniae N meningitidis and Listeria monocytogenes Streptococcus pneumoniae most common except neonatesMore than 75 of total cases are caused by N meningitidis Strep pneumoniae and Hinfluenzae combined
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CAUSES OF SEPTIC SEPTIC SEPTIC SEPTIC MENINGITIS
AGE Most common Others
Birth to 3 months Streptococcus agalactiae Escherichia coli L monocytogenes
3 to 60 months Streptococcuspneumoniae
Neisseria meningitidis
H influenzae type b
gt 60 months Streptococcuspneumoniae
Neisseria meningitidis
L monocytogenes
Other Gram negative
organisms
Any age (cranial
surgery)
Staphylococcus aureus
Any age
(immunosuppressed)
L monocytogenes
Other Gram negatives
(including P aeroginosa)
Bacterial Virulence FactorsNeisseria meningitidis
Capsule IgA protease pili and endotoxinHaemophilus influenzae
Capsule IgA protease pili and endotoxin Streptococcus pneumoniae
Capsule and IgA protease only
Neisseria meningitidisGram negative coffee bean shaped intracellular (PMNs) exclusively human pathogenMany members of the genus are commensals of upper respiratory tractAbout 30 of the population may transiently carry N meningitidis Responsible for more than 75 cases of septic meningitis ( Reported by Dr Jungkind) Transmission is via droplet inhalationMore than 13 of the cases occur in the first five years of ageHigh morbidity and mortality ~50 survivors have neurologic or other sequelae
DiagnosisClinical signs- rash (Tumbler test) sepsis fever nuchal rigidityCSF tap- protein glucose and WBC count
Culture- fastidious organism requires 5-10 CO2
Blood or CSF sample- plate on chocolate agarNasopharyngeal swab- plate on to Modified Martin-Thayer agar
Contains antibiotics to inhibit normal biotaRapid techniques
Latex agglutinationPCR
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PreventionTetravalent vaccine composed of Groups A C Y and W135 (Group B is weaklyimmunogenic)
Protection is group specificProtection is limited to ~3 yearsVaccination does not protect from carriage of the organism
Vaccine is poorly immunogenic for infants under 2 years of age
Streptococcus agalactiae Beta hemolytic Taxos A resistant Group B streptococcusNormal female genital organism (~40 colonized))60 mortality for babies who develop meningitis during the first week of life
Premature birth is an important risk factorNeonates
Lethargy fever sepsis and respiratory distressChildren and adults
Puerperal fever at delivery and other skin and soft tissue infections
Streptococcus pneumoniaeGram positive lancet shaped alpha hemolytic Taxos P sensitive cocci (Optochin)Part of normal flora of 20 adults and gt75 healthy childrenMOST COMMON cause of bacterial meningitisHighest cause of infantile meningitisMortality rate for pneumococcal meningitis is ~25Neurological sequelae is ~50
In elderly it may follow pneumoniaMiddle ear infectionsSinusiPathogenesis (Braun et al2002 J Clin Invest 10919-27)
Pathogenesis
Hydrogen peroxide- due to absence of catalase large amounts accumulate and enhanceapoptosisPneumolysin
pore forming toxinPotent neurotoxin can trigger cellular apoptosis
Pathogenesis (Guikel et al2003 PNAS10014363-14367)In mouse models invasion can occur through nasopharynx (not hematogenous)Teichoic and lipoteichoic acids of cell wall mediate binding to the gangliosides expressedon the neuronsSubsequent travel is then via retrograde axonal transport along olfactory neurons
Haemophilus influenzae
Gram negative fastidious encapsulated pleomorphic organismsSpread via blood from respiratory tract to the brainInfection opportunity between 4 months to 3 yearsGreater risk of permanent neurologic damage than any other bacterial meningitisVaccines made with type B capsular polysaccharide
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Enterobacteriaceae
Escherichia coli K1Gram negative facultative anaerobesDuring pregnancy increased colonization of K1 strain with 8 mortality
Spreads from nasopharynx to the meningesEnterobacteriaceae Symptoms
lt1 month old- irritability lethargy vomiting lack of appetite and seizures4-18 months- nuchal rigidity tense fontanels and feverOlder children amp adults- headache vomiting confusion lethargy seizures and feve
Interactions during meningitis
Escherichia coli GI respiratory orgenitourinary tract
bloodstream
Slide kindly provided by Dr J Rayner
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Klebsiella pneumoniaeGram negative rodsHigh incidence in cockroach infested areasEarly onset- lt3 days- 2nd only to GBS
(leukopenia and neutropenia)Late onset- 8-28 days-2nd only to Staphylococcus
(leukocytosis and neutrophilia)Symptoms
Lethargy poor feeding little cry fever scleremaCulture from blood CSF urineC-reactive protein positive
Listeria monocytogenesGram positive non spore forming aerobic motile rodsEpidemiology
Food-borne (dairy and deli)Soil water decaying vegetation
Human intestines may be reservoir
2-12 humans carry the organismCan be transmitted to the baby during delivery (may cause spontaneous abortions)Pathogenesis
Grows in macrophagesReleases ldquoInternalinrdquo- as a cell attachment molecule trigger entryListeriolysin- protein that helps in movement within the cellHemolysin- pore-forming toxin Allows escape from phagosome to the phagosoleUses host cell actin to move to the new cells
DiagnosisIntracellular gram positive rods in macrophages and neutrophilsCSF culture- looks like β-Strep but catalase + and ldquotumblerdquo
Slide is kindly provided by Dr Rayner
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Spirochetes Infections of CNSTreponema pallidum
Early stages are infectious and no CNS involvementTakes about 10 year or longer for non treated cases
Neurosyphilis is the Tertiary stage of the disease and no longer infectiousDelayed hypersensitivity is part of the pathologic mechanism of tissue damageCommonly found in different tissues of the body as ldquoGummasrdquoInfection of CNS is via meningovascular routeSpirochetes Infections of CNSSymptoms
CNS degenerative changes resulting in mental changesMay have frank psychosisShuffling gait ldquotabes dorsalisrdquo
DiagnosisSpinal fluid may be helpfulElevated WBCs and protein
VDRL positive
Leptospira interogans Animals are reservoirsSpreads through animal urine contaminated water and food (survives weeks in water)No body of water in the US is free from itSensitive to Acid pH drying and soap~100 casesyearSewer workers miners veterinarians and meat packers are at risk Spirochetes Infections of CNSSymptoms
Incubation 7-13 days (range 5 days - 4 weeks)
Bacteremic phase- influenza like symptoms and fever (bacteria NOW enter the CNS)2 nd Phase - ~3+weeksHeadache with ldquoasepticrdquo meningitisSometimes hemodynamic collapse
DiagnosisBlood cultureCSF analysis and cultureRise in antibody between acute and convalescent stages
Borrelia burgdorferi~15 Neurologic abnormalities rarely fatal
Starts with a tick biteLarge spirochetes- 02x10-30 micromSpirochetes Infections of CNS
SymptomsClassic ldquobullrsquos eyerdquo rash fever joint pain meningeal irritation2nd Stage- dissemination system wide3rd Stage- mild neurologic or frank encephalitis
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DiagnosisLoose irregular spirals Silver or immunoflourescent stainDifficult to cultureCDC recommends antibody screen using ELISA
Fungal Infections of CNSDisseminate hematogenously from a remote site of infection (oropharynx or lung)Create multiple areas of infection within brain and other organsCan cause abscessesMeningoencephalitis occurs early by vascular invasion by fungusCan see secondary thrombosis cerebral infarction and hemorrhages
Common fungiCandida albicansCryptococcus neoformansHistoplasma capsulatumAspergillus fumigatus
DiagnosisAntibody studiesCXRCandida- forms granulomatus reaction Yeast forms seen with silver stainCryptococcus- fungi appear like encapsulated spheres Capsules can be seen bymucicarmine stain Histoplasma- CT scan Aspergillus- branching hyphae classical appearance
Please revisit your notes on Respiratory fungal infections by Dr Lennon
Encephalitis
EtiologyViral
Herpes viruses enteroviruses arboviruses rabies virus HIV HTLV-1Paramyxoviruses (mumps rubeola virus and arenaviruses)
Bacterial (RARE)Exceptions Legionella pneumoniae Borrelia burgdorferi Treponema pallidum
FungalCryptococcus neoformans
ParasiticPlasmodium falciparum Trypanosomes
MyelitisAcute inflammation of the spinal cord
Depending upon virus this can lead to flaccid paralysisSymptoms
HeadacheFeverIrritation followed by
Weakness of one or more extremitiesEtiology
Poliovirus was the leading cause before vaccinationWest Nile virus is the most significant after 2000
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Defined as inflammation of brain parenchymaEncephalitis is considered clinically a more severe syndrome than viral meningitisSymptoms
HeadacheFever
Altered consciousness-lethargy to confusion and comaBehavioral and speech disturbanceSeizures
Arboviruses Arthropod-borne viral infectionsDistributed worldwideTransmitted by mosquitoes and ticksSporadic and epidemic encephalitisSeizures are generally the complications in children
All arboviruses are enveloped viruses with icosahedral nucleocapsid and contain a transfecting RNA
Major families of arboviruses (Togaviridae and Flaviviridae )Togaviridae
Belongs to Baltimore Class IVbEarly and late proteins madeVirus buds at the plasma membrane
TogaviridaeVenezuelan Equine Encephalitis (VEE)Togaviridae (alphavirus)
Spread through Culex and Aedes mosquitoesSymptoms
Prodrome- fever chills weakness headache myalgia (due to viral replication )Rapid progression- nuchal rigidity confusion somnolence seizure in 50 of cases andcoma (due to spread through microvascular permeability of brain then cell-to-celloccurs via axon and dendrites )NO DEATHS in humans 80 mortality in horses
Eastern Equine Encephalitis (EEE)Common in North AmericaSpreads through Aedes and Culiseta spHumans are dead-end hosts but Aedes may spread from horse to human
Clinical symptoms similar to that of VEEHIGH MORTALITY in humans
Western Equine Encephalitis (WEE)Spreads through Culex and CulisetaCommon in rural areas of US in summer monthsFatality rate 3-4 death in 1-2 days Children have a 30 chance of CNS sequelae
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Pathophysiology of Equine EncephalitidesDefuse CNS involvementNeutrophils and macrophages infiltrate brain parenchyma causing focal necrosis and spottydemyelinationVascular inflammation with endothelial proliferation and small vessel thrombosis
EEELarge number of active virus entering in brain parenchymaEffects the perikaryon and dendrites of neurons with minimal glial cell infiltration
WEEDamage mediated by large number of immunologically active cells that enterbrainCell death by apoptosis primarily in the glial and inflammatory cells
FlaviviridaeBelongs to Baltimore class IVaPolyprotein is translated first which cleaves into many individual proteinsVirus buds inside cytoplasmic vesicles and the virus is released through
exocytosis
St Louis Encephalitis virus (SLE)Epidemiology
Transmitted by culex mosquitoesOvert infection depends upon
Efficiency of replication at extra neural sitesDegree of viremiaAge of the host
PathophysiologyVirus enters through BBB (astrocyte complex)
Or cross fenestrated endothelium (choroid plexus)Symptoms
Mortality 2-20 (higher in elderly)Malaise and fever only 20 develop sequelae (irritability memory loss movementdisorders motor deficits)Seizures and coma COMMONNo chronic illness
Japanese B Encephalitis virus (JBE)Epidemiology
Spread through Culex mosquitoesIncubation 4-14 days
Rural areas of AsiaSeptember 2010 India 319 deaths and Nepal 5 deaths
SymptomsViral prodrome- fever by 2nd weekEncephalitis syndrome with tremors NOT seizuresLow CSF IgGIgM ratio= higher death rate
West Nile Encephalitis virus (WNV)Epidemiology
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Wild birds are reservoir spreads through Aedes mosquitoes3-15 fatalVery RARE person to person transmission
SymptomsViral prodrome with maculopapular rash on trunk and extremitiesHeadache HIGH fever nuchal rigidity stupor tremor and seizures paralysis
BunyaviridaeAt least 200 different viruses included in this groupEnveloped viruses containing single-stranded negative polarity segmented (3) RNASpreads through mosquitoes ticks and flies
California Encephalitis virusLa Crosse virus
RhabdoviridaeLyssavirus RabiesStructure
Bullet shaped virusSingle-stranded negative polarity RNA
Helical nucleocapsid in an envelope5 proteins- NPMG and L
Surface glycoprotein attaches to cell receptors including Acetylcholine receptor atneuromuscular junctions
PathophysiologyViral entry into the cell is via endocytosisVirus has a preference for nerve and salivary gland cells (travels via axons to CNS)Spreads from brain to salivary glands kidneys and conjunctival cells (virus in tears )
EpidemiologyEstimated 35000-50000 cases worldwide
Highest in Asia ~90 casesEndozoonotic all warm blooded animals are susceptible
Urban- dogs and catsSylvatic- wildlife
SymptomsIncubation 20-90 days may extend to a yearNonspecific ndash general malaise fever headache (tingling pain and weakness at the bitsite)Progressive - neurologic symptoms including insomnia confusion slight or partialparalysis agitation hypersalivation dysphagia (hydrophobia)Paralytic ndashdisorientation stupor
Death within days after symptoms (~7 days)Diagnosis
Saliva- virus isolation RT-PCRSerum and CSF for rabies antibodies (FA and ELISA)Brain tissue- Negri bodies Babes nodules consisting of glial cells
TreatmentPrevention
Wash all wounds with soap and water
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1 dose of immune globulin and 4 doses of vaccine on days 137 amp14 days + 2boosters on days 0 and 3
New recommendations by CDC published on Mar 18 2010
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010(MMWR VOL59RR2 MAR 18 2010)
NOT PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent (eg povidine-iodinesolution) should be used to irrigate the wounds
Human rabies
immune globulin(HRIG)
Administer 20 IUkg body weight If anatomicallyfeasible the full dose should be infiltrated around and
into the wound(s) and any remaining volume shouldbe administered at an anatomical site (intramuscular
[IM]) distant from vaccine administration
Vaccine Human diploid cell vaccine (HDCV) or purified chickembryo cell vaccine (PCECV) 10 mL IM (deltoid but
never in the gluteal region) 1 each on days 0 3 7 and
14(For immunocompromised 5 shots)
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010
(MMWR VOL59RR2 MAR 18 2010)
PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent such as povidine-iodinesolution should be used to irrigate the wounds
HRIG HRIG should not be administered
Vaccine HDCV or PCECV 10 mL IM (deltoid but never in the
gluteal area) 1 each on days 0 and 3
For persons with immunosuppression rabies PEPshould be administered using all 5 doses of vaccine on
days 0 3 7 14 and 28
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Other virus infections of the CNSArenaviridae - Lymphocytic ChoriomeningitisTogaviridae- Rubella virusHerpesviridae - Human Herpes virus 1-8Retroviridae - HIV-1Other virus infections of the CNS
Papovaviridae - Polyoma virus (JC virus)-PML (Progressive Multifocal Leukoencephalopathy)Viral DNA in majority of healthy humansMultifocal signs including hemiparesis visual loss seizures dementia personalitychanges and gait problemsCharacteristic white matter lesions common in posterior occipital area
Paramyxoviridae - Mumps viruses and Measles- SSPE (Subacute Sclerosing Pan Encephalitis)Slow fatal condition after more than 10 years of measlesWorldwide more common in boys (31) than girlsBehavior changes in school age childrenFulminant course- 10 of cases death in 3 monthsChronic course- death in 4-10 years
Brain Abscess and EmpyemaLocalized bacterial infection of brain parenchyma and subdural or epidural spacesPressure from accumulation of exudates may permanently damage the brain tissueMay be fatal if not treated properlyAbscess
Fixed boundariesEmpyema
Lack of definable shape or sizeBrain Abscess
Symptoms
Usually are rapid and associated with their locationHeadacheChanges in mental status- drowsiness to comaGeneralized seizure
Fungal brain abscessDisseminated hematogenously from remote site ( lungs or oropharynx)Create multiple areas of infection within brainMeningoencephalitis occurs early by vascular invasionEtiology
Aspergillus Cryptococcus Candida
Transmissible Spongiform EncephalopathiesPrion is an abnormal isomer of normal host proteinNO NUCLEIC ACID presentReplicate without provoking antibody or inflammatory responseAre resistant to some inactivation methods used for bacteria and viruses (70 alcohol X-raysand UV light etc)Sensitive to autoclaving and bleachDisease confined to the CNS and may take decades to manifestCan be inherited (~15) of cases)
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PathogenesisNormal PrPc- glycoprotein with secondary structures dominated by Alpha helixPrion protein PrPSc- glycoprotein with secondary structures dominated by Beta-pleats When PrPSc molecules comes in contact with the normal PrPc molecule the normal PrPc changes into the abnormal PrPSc
Modified protein aggregates in neurons as myeloid plaques
Spongy appearance of cerebrum is due to the formation of vacuoles in the cortex andcerebellum
Spread of PrionsSporadic- no apparent causeInherited - through autosomal dominant traitIngestion - infected food cannibalism
Kuru-incubation ~20 yearsInvolves progressive trunchal shaking and unsteady gait Death within 3-24 months
Medical events- (Iatrogenic) through surgery organs etc
Creutzfeld Jekob Disease (CJD)Most common prion human diseasePeak incidence 55-65 years but can affect teenagersNo treatmentSymptoms
Insidious mental deteriorationEarly cerebellar and visual problemsSevere dementia in 6 monthsBrain and lower motor neuron involvementCases of CJD have been due to
Infected corneal transplantsReused improperly sterilized brain surgery equipment
Pituitary hormone injections derived from cadaversAccidental cuts during autopsies or surgeries
Bovine Variant of CJDBSE re-emerged in 1996 with progressive neurodegenerative disease resulting in patient deathNormally bovine but crossed to humans as Mad Cow DiseaseDiagnosis
Biopsy of BrainSpongiform encephalopathyAccumulation of abnormally folded protein
Sporadic diseaseCSF- no cells
CNS InfectionsThis was by no means a complete inventory of infectious agents involvedThere are many more however we discussed ONLY the very common and frequent infectionsThe original Mad Cow
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Most common- Staph aureusImmunodeficient or HIV infections- Nocardia Aspergillus Candida
Most likely through Choroid plexus as it is highly vascularized inflammation may increase entryinto CNSDirect extension
Infections of teeth middle ear or mastoids or sinuses
Most common etiologyAerobic and anaerobic streptococciBacteroidesEnterobacteriaceaePsudomadsFusibacteriumPeptococcus
Etiology depends upon location of the source of infectionMouth- mixed biotaLungs- Streptococci Fusibaterium Corynebacterium Peptococcus spHeart- Strep viridans Staph aureusUrinary tract- Enterobacteriaceae Pseudomonas
Wounds- Staph aureus
CNS SyndromesMeningitis
Acute Meningitis- viral or bacterialChronic Meningitis- fungi and tubercle bacilli
Encephalitis- viralMyelitis- viralBrain Abscesses
Acute Brain Abscess- generally poly microbialChronic Brain Abscess- tubercle bacilli fungi and protozoa
MeningitisInfection of the membranes and fluid surrounding the brain and spinal cord (spinalmeningitis) causing inflammation of the meninges
MeningismGroup of Symptoms and signs associated with the inflammation
HeadacheNuchal rigidityNausea and vomitingPhotophobia
Tests for MeningismDemonstrate inability to flex the neck and touch the chin to the chest
Demonstrate inability to oppose the nose with the kneesTripod sign- inability to sit without making a tripod with handsKernigrsquos sign- patientrsquos leg can not be straightened because of hamstring spasmBrudzinskirsquos neck sign- patient retracts the legs when neck is liftedSymptoms associated with MeningitisDepend upon age microorganism and the route to meninges
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Early symptoms (nonspecific)FeverMalaiseAches and painsNauseaVomiting
Headache
HALL MARKS of Meningitis
Symptoms associated with MeningitisDiagnosis of CNS infectionsCerebrospinal Fluid
Chemical and cellular analysisCulturePCR
FEATURES OF CSF
Etiology Leukocytes
(mm3)
Neutrophils
Glucose
(mgdL)
Protein
(mgdL)
Normal 0-6 0 40-80 20-50
Meningitis
Acute Bacterial
gt1000 gt50 0-10 gt100
Viral 10-1000Usually lt300
High for 24hrs then lt50
40-80 50-100
Chronic Mycobact
amp Fungal
100-500 lt10 le40 gt100
(Mycobact)
50-100
(Fungal)
Encephalitis Viral 10-500 High for 24
hrs then lt50
40-80 50-100
BrainAbscess
Bacterial
Fungal
10-100 lt50 40-80 50-100
10-500 RBCs in HHV-1 Infection A Qureshi S2010
Neuroimaging
Helpful in partial differentiation of viral encephalitisJapanese B virus grey matter involvementNipah virus multiple small white matter lesionsHuman herpes virus-1 hemorrhagesAbscesses and Empyema differentiation
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MeningitisInflammation of the meninges occurs due to viral or bacterial infectionsAseptic
Over 50 of the cases are due to a variety of virusesRest of the cases are due to bacteria with special growth requirements or slow growers
CAUSES OF ASEPTIC ASEPTIC ASEPTIC ASEPTIC MENINGITIS
Viruses Bacteria
Common Enteroviruses
Arboviruses
HHV-2
Borrelia burgdorferi
Inadequately treated bacterial
meningitis
Uncommon Mumps
HHV-5 (CMV)
HHV-6
HIV
Mycobacterium tuberculosis
Leptospira sp
Micoplasma pneumoniae
Incidence varies with the region
Modified from Neurol Clin 2008 26635
A Qureshi S10
Viral Infections of CNS
Viruses use at least two pathways to enter the CNSHematogenous (most common)Neural
Through Olfatory nerve- HHV-1amp2Intra-axonal through neuron route- Rabies
Direct injuryViral infections range from meningitis to myelitis
Viral Meningitis Common causes of Aseptic meningitis
Enteroviruses ( ECHO) coxsackie and poliovirusHerpes virus and other viruses are less common
Mumps virus meningitis is a complication of infectionCSF findings
Glucose ndashnormalProtein- moderately highWBC count- increased predominantly lymphocytes
Gram stain- NO BACTERIA
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EnterovirusesEnteroviruses belong to family PicornavirideaNaked small (25-30 nm) icoshedral virusesResistant to pH 3-9 detergents and heatContain single-stranded positive polarity RNA
Transfecting viruses
Baltimore Class IVa RNA replication in cytoplasmMost viruses are CytolyticOver 63 serotypes involved in meningitisPoliovirus has only 3 serotypes and may cause meningitis to myelitisEradicated from the Western Hemisphere through OPV
More than 90 of viral meningitis cases are due to EnterovirusesOther syndromes caused by enteroviruses include
Hand-foot and mouth diseaseHerpanginaMyocarditisPleurodynia
Acute hemorrhagic conjunctivitis
Clinical syndromes are determined byVirus class and serotypeTissue tropismInfectious dosePortal of entryPatient age sex Immune competence
EpidemiologyWorldwide distributionHumans are the only reservoir
Asymptomatic infections are commonShow seasonality
Temperate climates- Summer to Fall (water)Tropical climates- year-round (fecal-oral)Infants and children MOST susceptible
Please refer to Murray et al (6 th Ed)Box 56-4 p 556
PoliovirusesMember of family PicornaviridaeSame viral characters as that of EnterovirusesSpreads through fecal-oral route by consuming contaminated food and waterThrough direct contact with infected stool or throat secretions
Symptoms common to those of meningeal irritationHeadache fever nuchal rigidity followed by weakness in one or more extremities
Clinical syndromeAcute Flaccid Paralysis due to infection of anterior horn of grey matter
PathogenesisInfects enterocytes of the GI tractTransverses intestinal wall through basement membrane
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Moves into gut-associated lymphoid tissue eg Peyerrsquos patches (site of primaryreplication)Resulting viremia seeds peripheral tissue virus enters the neurons of the peripheralnervous system that innervates the peripheral tissues and the virus traffics to the CNSusing retrograde axonal transport
(Lancaster and Pfeiffer 2010)
Outcomes of infectionInapparent infections
95 asymptomatic virus in RESDiagnosis by virus isolation from feces and oropharynx and by specific serumantibodies
Abortive polio (minor illness)- flu like symptomsSimilar to any systemic viral infection
Polio encephalitis- RARENon-paralytic polio (aseptic meningitis)
Similar to other enteroviral meningitis
Paralytic polio (lt2 of cases)Viral spread is normally restricted due to
Limited replication of virus in peripheral neuronsInsufficient retrograde axonal transport in peripheral neuronsInnate resistance through IFN α β production
When these barriers are breeched the out come will be paralytic polioSpinal - flaccid paralysis due lysis of the anterior horn cellsBulbar - paralysis of cranial nerve IX and X medullarrespiratory centers
PreventionInactivated vaccine
Formalized Salk vaccine injected im
Local antibody is not producedMostly used in Western Hemisphere (where polio is considered eradicated)
Please see Table 56-2 in Murray et al 6 th Ed p 561 Live oral vaccine
Sabin vaccine is stable at room temperature with MgCl2Produces secretory antibodiesVirus can spread to contacts and enhance herd immunity and may causeparalytic polio (~1 in 4 million)
Please see Table 56-2 in Murray et al 6 th Ed p 561
Meningitis (Continued)
Septic (as opposed to viral Aseptic) Caused by bacteria onlyAssociated with high Mortality and SeverityEtiology is AGE dependent
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CAUSES OF SEPTIC SEPTIC SEPTIC SEPTIC MENINGITIS
AGE Most common Others
Birth to 3 months Streptococcus agalactiae Escherichia coli L monocytogenes
3 to 60 months Streptococcuspneumoniae
Neisseria meningitidis
H influenzae type b
gt 60 months Streptococcuspneumoniae
Neisseria meningitidis
L monocytogenes
Other Gram negative
organisms
Any age (cranial
surgery)
Staphylococcus aureus
Any age
(immunosuppressed)
L monocytogenes
Other Gram negatives
(including P aeroginosa)
Bacterial Infections of CNSOver 25 infectious agents involvedSevere life threatening infections requiring prompt diagnosis and treatmentSeptic meningitis (Bacterial meningitis)Bacterial invasion into CNS
Invasion from nearby siteMiddle ear or chronic sinusitis
Spread from a distant siteHematogenous invasion
Direct introductionRARE sometimes the source cannot be identified
Bacterial MeningitisNeonates- Strep agalactiae Coliforms and Listeria monocytogenesInfants- Streptococcus pneumoniae Neisseria meningitidis and H influenzaeChildren- Strep pneumoniae N meningitidis and Listeria monocytogenes Streptococcus pneumoniae most common except neonatesMore than 75 of total cases are caused by N meningitidis Strep pneumoniae and Hinfluenzae combined
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CAUSES OF SEPTIC SEPTIC SEPTIC SEPTIC MENINGITIS
AGE Most common Others
Birth to 3 months Streptococcus agalactiae Escherichia coli L monocytogenes
3 to 60 months Streptococcuspneumoniae
Neisseria meningitidis
H influenzae type b
gt 60 months Streptococcuspneumoniae
Neisseria meningitidis
L monocytogenes
Other Gram negative
organisms
Any age (cranial
surgery)
Staphylococcus aureus
Any age
(immunosuppressed)
L monocytogenes
Other Gram negatives
(including P aeroginosa)
Bacterial Virulence FactorsNeisseria meningitidis
Capsule IgA protease pili and endotoxinHaemophilus influenzae
Capsule IgA protease pili and endotoxin Streptococcus pneumoniae
Capsule and IgA protease only
Neisseria meningitidisGram negative coffee bean shaped intracellular (PMNs) exclusively human pathogenMany members of the genus are commensals of upper respiratory tractAbout 30 of the population may transiently carry N meningitidis Responsible for more than 75 cases of septic meningitis ( Reported by Dr Jungkind) Transmission is via droplet inhalationMore than 13 of the cases occur in the first five years of ageHigh morbidity and mortality ~50 survivors have neurologic or other sequelae
DiagnosisClinical signs- rash (Tumbler test) sepsis fever nuchal rigidityCSF tap- protein glucose and WBC count
Culture- fastidious organism requires 5-10 CO2
Blood or CSF sample- plate on chocolate agarNasopharyngeal swab- plate on to Modified Martin-Thayer agar
Contains antibiotics to inhibit normal biotaRapid techniques
Latex agglutinationPCR
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PreventionTetravalent vaccine composed of Groups A C Y and W135 (Group B is weaklyimmunogenic)
Protection is group specificProtection is limited to ~3 yearsVaccination does not protect from carriage of the organism
Vaccine is poorly immunogenic for infants under 2 years of age
Streptococcus agalactiae Beta hemolytic Taxos A resistant Group B streptococcusNormal female genital organism (~40 colonized))60 mortality for babies who develop meningitis during the first week of life
Premature birth is an important risk factorNeonates
Lethargy fever sepsis and respiratory distressChildren and adults
Puerperal fever at delivery and other skin and soft tissue infections
Streptococcus pneumoniaeGram positive lancet shaped alpha hemolytic Taxos P sensitive cocci (Optochin)Part of normal flora of 20 adults and gt75 healthy childrenMOST COMMON cause of bacterial meningitisHighest cause of infantile meningitisMortality rate for pneumococcal meningitis is ~25Neurological sequelae is ~50
In elderly it may follow pneumoniaMiddle ear infectionsSinusiPathogenesis (Braun et al2002 J Clin Invest 10919-27)
Pathogenesis
Hydrogen peroxide- due to absence of catalase large amounts accumulate and enhanceapoptosisPneumolysin
pore forming toxinPotent neurotoxin can trigger cellular apoptosis
Pathogenesis (Guikel et al2003 PNAS10014363-14367)In mouse models invasion can occur through nasopharynx (not hematogenous)Teichoic and lipoteichoic acids of cell wall mediate binding to the gangliosides expressedon the neuronsSubsequent travel is then via retrograde axonal transport along olfactory neurons
Haemophilus influenzae
Gram negative fastidious encapsulated pleomorphic organismsSpread via blood from respiratory tract to the brainInfection opportunity between 4 months to 3 yearsGreater risk of permanent neurologic damage than any other bacterial meningitisVaccines made with type B capsular polysaccharide
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Enterobacteriaceae
Escherichia coli K1Gram negative facultative anaerobesDuring pregnancy increased colonization of K1 strain with 8 mortality
Spreads from nasopharynx to the meningesEnterobacteriaceae Symptoms
lt1 month old- irritability lethargy vomiting lack of appetite and seizures4-18 months- nuchal rigidity tense fontanels and feverOlder children amp adults- headache vomiting confusion lethargy seizures and feve
Interactions during meningitis
Escherichia coli GI respiratory orgenitourinary tract
bloodstream
Slide kindly provided by Dr J Rayner
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Klebsiella pneumoniaeGram negative rodsHigh incidence in cockroach infested areasEarly onset- lt3 days- 2nd only to GBS
(leukopenia and neutropenia)Late onset- 8-28 days-2nd only to Staphylococcus
(leukocytosis and neutrophilia)Symptoms
Lethargy poor feeding little cry fever scleremaCulture from blood CSF urineC-reactive protein positive
Listeria monocytogenesGram positive non spore forming aerobic motile rodsEpidemiology
Food-borne (dairy and deli)Soil water decaying vegetation
Human intestines may be reservoir
2-12 humans carry the organismCan be transmitted to the baby during delivery (may cause spontaneous abortions)Pathogenesis
Grows in macrophagesReleases ldquoInternalinrdquo- as a cell attachment molecule trigger entryListeriolysin- protein that helps in movement within the cellHemolysin- pore-forming toxin Allows escape from phagosome to the phagosoleUses host cell actin to move to the new cells
DiagnosisIntracellular gram positive rods in macrophages and neutrophilsCSF culture- looks like β-Strep but catalase + and ldquotumblerdquo
Slide is kindly provided by Dr Rayner
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Spirochetes Infections of CNSTreponema pallidum
Early stages are infectious and no CNS involvementTakes about 10 year or longer for non treated cases
Neurosyphilis is the Tertiary stage of the disease and no longer infectiousDelayed hypersensitivity is part of the pathologic mechanism of tissue damageCommonly found in different tissues of the body as ldquoGummasrdquoInfection of CNS is via meningovascular routeSpirochetes Infections of CNSSymptoms
CNS degenerative changes resulting in mental changesMay have frank psychosisShuffling gait ldquotabes dorsalisrdquo
DiagnosisSpinal fluid may be helpfulElevated WBCs and protein
VDRL positive
Leptospira interogans Animals are reservoirsSpreads through animal urine contaminated water and food (survives weeks in water)No body of water in the US is free from itSensitive to Acid pH drying and soap~100 casesyearSewer workers miners veterinarians and meat packers are at risk Spirochetes Infections of CNSSymptoms
Incubation 7-13 days (range 5 days - 4 weeks)
Bacteremic phase- influenza like symptoms and fever (bacteria NOW enter the CNS)2 nd Phase - ~3+weeksHeadache with ldquoasepticrdquo meningitisSometimes hemodynamic collapse
DiagnosisBlood cultureCSF analysis and cultureRise in antibody between acute and convalescent stages
Borrelia burgdorferi~15 Neurologic abnormalities rarely fatal
Starts with a tick biteLarge spirochetes- 02x10-30 micromSpirochetes Infections of CNS
SymptomsClassic ldquobullrsquos eyerdquo rash fever joint pain meningeal irritation2nd Stage- dissemination system wide3rd Stage- mild neurologic or frank encephalitis
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DiagnosisLoose irregular spirals Silver or immunoflourescent stainDifficult to cultureCDC recommends antibody screen using ELISA
Fungal Infections of CNSDisseminate hematogenously from a remote site of infection (oropharynx or lung)Create multiple areas of infection within brain and other organsCan cause abscessesMeningoencephalitis occurs early by vascular invasion by fungusCan see secondary thrombosis cerebral infarction and hemorrhages
Common fungiCandida albicansCryptococcus neoformansHistoplasma capsulatumAspergillus fumigatus
DiagnosisAntibody studiesCXRCandida- forms granulomatus reaction Yeast forms seen with silver stainCryptococcus- fungi appear like encapsulated spheres Capsules can be seen bymucicarmine stain Histoplasma- CT scan Aspergillus- branching hyphae classical appearance
Please revisit your notes on Respiratory fungal infections by Dr Lennon
Encephalitis
EtiologyViral
Herpes viruses enteroviruses arboviruses rabies virus HIV HTLV-1Paramyxoviruses (mumps rubeola virus and arenaviruses)
Bacterial (RARE)Exceptions Legionella pneumoniae Borrelia burgdorferi Treponema pallidum
FungalCryptococcus neoformans
ParasiticPlasmodium falciparum Trypanosomes
MyelitisAcute inflammation of the spinal cord
Depending upon virus this can lead to flaccid paralysisSymptoms
HeadacheFeverIrritation followed by
Weakness of one or more extremitiesEtiology
Poliovirus was the leading cause before vaccinationWest Nile virus is the most significant after 2000
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Defined as inflammation of brain parenchymaEncephalitis is considered clinically a more severe syndrome than viral meningitisSymptoms
HeadacheFever
Altered consciousness-lethargy to confusion and comaBehavioral and speech disturbanceSeizures
Arboviruses Arthropod-borne viral infectionsDistributed worldwideTransmitted by mosquitoes and ticksSporadic and epidemic encephalitisSeizures are generally the complications in children
All arboviruses are enveloped viruses with icosahedral nucleocapsid and contain a transfecting RNA
Major families of arboviruses (Togaviridae and Flaviviridae )Togaviridae
Belongs to Baltimore Class IVbEarly and late proteins madeVirus buds at the plasma membrane
TogaviridaeVenezuelan Equine Encephalitis (VEE)Togaviridae (alphavirus)
Spread through Culex and Aedes mosquitoesSymptoms
Prodrome- fever chills weakness headache myalgia (due to viral replication )Rapid progression- nuchal rigidity confusion somnolence seizure in 50 of cases andcoma (due to spread through microvascular permeability of brain then cell-to-celloccurs via axon and dendrites )NO DEATHS in humans 80 mortality in horses
Eastern Equine Encephalitis (EEE)Common in North AmericaSpreads through Aedes and Culiseta spHumans are dead-end hosts but Aedes may spread from horse to human
Clinical symptoms similar to that of VEEHIGH MORTALITY in humans
Western Equine Encephalitis (WEE)Spreads through Culex and CulisetaCommon in rural areas of US in summer monthsFatality rate 3-4 death in 1-2 days Children have a 30 chance of CNS sequelae
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Pathophysiology of Equine EncephalitidesDefuse CNS involvementNeutrophils and macrophages infiltrate brain parenchyma causing focal necrosis and spottydemyelinationVascular inflammation with endothelial proliferation and small vessel thrombosis
EEELarge number of active virus entering in brain parenchymaEffects the perikaryon and dendrites of neurons with minimal glial cell infiltration
WEEDamage mediated by large number of immunologically active cells that enterbrainCell death by apoptosis primarily in the glial and inflammatory cells
FlaviviridaeBelongs to Baltimore class IVaPolyprotein is translated first which cleaves into many individual proteinsVirus buds inside cytoplasmic vesicles and the virus is released through
exocytosis
St Louis Encephalitis virus (SLE)Epidemiology
Transmitted by culex mosquitoesOvert infection depends upon
Efficiency of replication at extra neural sitesDegree of viremiaAge of the host
PathophysiologyVirus enters through BBB (astrocyte complex)
Or cross fenestrated endothelium (choroid plexus)Symptoms
Mortality 2-20 (higher in elderly)Malaise and fever only 20 develop sequelae (irritability memory loss movementdisorders motor deficits)Seizures and coma COMMONNo chronic illness
Japanese B Encephalitis virus (JBE)Epidemiology
Spread through Culex mosquitoesIncubation 4-14 days
Rural areas of AsiaSeptember 2010 India 319 deaths and Nepal 5 deaths
SymptomsViral prodrome- fever by 2nd weekEncephalitis syndrome with tremors NOT seizuresLow CSF IgGIgM ratio= higher death rate
West Nile Encephalitis virus (WNV)Epidemiology
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Wild birds are reservoir spreads through Aedes mosquitoes3-15 fatalVery RARE person to person transmission
SymptomsViral prodrome with maculopapular rash on trunk and extremitiesHeadache HIGH fever nuchal rigidity stupor tremor and seizures paralysis
BunyaviridaeAt least 200 different viruses included in this groupEnveloped viruses containing single-stranded negative polarity segmented (3) RNASpreads through mosquitoes ticks and flies
California Encephalitis virusLa Crosse virus
RhabdoviridaeLyssavirus RabiesStructure
Bullet shaped virusSingle-stranded negative polarity RNA
Helical nucleocapsid in an envelope5 proteins- NPMG and L
Surface glycoprotein attaches to cell receptors including Acetylcholine receptor atneuromuscular junctions
PathophysiologyViral entry into the cell is via endocytosisVirus has a preference for nerve and salivary gland cells (travels via axons to CNS)Spreads from brain to salivary glands kidneys and conjunctival cells (virus in tears )
EpidemiologyEstimated 35000-50000 cases worldwide
Highest in Asia ~90 casesEndozoonotic all warm blooded animals are susceptible
Urban- dogs and catsSylvatic- wildlife
SymptomsIncubation 20-90 days may extend to a yearNonspecific ndash general malaise fever headache (tingling pain and weakness at the bitsite)Progressive - neurologic symptoms including insomnia confusion slight or partialparalysis agitation hypersalivation dysphagia (hydrophobia)Paralytic ndashdisorientation stupor
Death within days after symptoms (~7 days)Diagnosis
Saliva- virus isolation RT-PCRSerum and CSF for rabies antibodies (FA and ELISA)Brain tissue- Negri bodies Babes nodules consisting of glial cells
TreatmentPrevention
Wash all wounds with soap and water
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1 dose of immune globulin and 4 doses of vaccine on days 137 amp14 days + 2boosters on days 0 and 3
New recommendations by CDC published on Mar 18 2010
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010(MMWR VOL59RR2 MAR 18 2010)
NOT PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent (eg povidine-iodinesolution) should be used to irrigate the wounds
Human rabies
immune globulin(HRIG)
Administer 20 IUkg body weight If anatomicallyfeasible the full dose should be infiltrated around and
into the wound(s) and any remaining volume shouldbe administered at an anatomical site (intramuscular
[IM]) distant from vaccine administration
Vaccine Human diploid cell vaccine (HDCV) or purified chickembryo cell vaccine (PCECV) 10 mL IM (deltoid but
never in the gluteal region) 1 each on days 0 3 7 and
14(For immunocompromised 5 shots)
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010
(MMWR VOL59RR2 MAR 18 2010)
PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent such as povidine-iodinesolution should be used to irrigate the wounds
HRIG HRIG should not be administered
Vaccine HDCV or PCECV 10 mL IM (deltoid but never in the
gluteal area) 1 each on days 0 and 3
For persons with immunosuppression rabies PEPshould be administered using all 5 doses of vaccine on
days 0 3 7 14 and 28
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Other virus infections of the CNSArenaviridae - Lymphocytic ChoriomeningitisTogaviridae- Rubella virusHerpesviridae - Human Herpes virus 1-8Retroviridae - HIV-1Other virus infections of the CNS
Papovaviridae - Polyoma virus (JC virus)-PML (Progressive Multifocal Leukoencephalopathy)Viral DNA in majority of healthy humansMultifocal signs including hemiparesis visual loss seizures dementia personalitychanges and gait problemsCharacteristic white matter lesions common in posterior occipital area
Paramyxoviridae - Mumps viruses and Measles- SSPE (Subacute Sclerosing Pan Encephalitis)Slow fatal condition after more than 10 years of measlesWorldwide more common in boys (31) than girlsBehavior changes in school age childrenFulminant course- 10 of cases death in 3 monthsChronic course- death in 4-10 years
Brain Abscess and EmpyemaLocalized bacterial infection of brain parenchyma and subdural or epidural spacesPressure from accumulation of exudates may permanently damage the brain tissueMay be fatal if not treated properlyAbscess
Fixed boundariesEmpyema
Lack of definable shape or sizeBrain Abscess
Symptoms
Usually are rapid and associated with their locationHeadacheChanges in mental status- drowsiness to comaGeneralized seizure
Fungal brain abscessDisseminated hematogenously from remote site ( lungs or oropharynx)Create multiple areas of infection within brainMeningoencephalitis occurs early by vascular invasionEtiology
Aspergillus Cryptococcus Candida
Transmissible Spongiform EncephalopathiesPrion is an abnormal isomer of normal host proteinNO NUCLEIC ACID presentReplicate without provoking antibody or inflammatory responseAre resistant to some inactivation methods used for bacteria and viruses (70 alcohol X-raysand UV light etc)Sensitive to autoclaving and bleachDisease confined to the CNS and may take decades to manifestCan be inherited (~15) of cases)
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PathogenesisNormal PrPc- glycoprotein with secondary structures dominated by Alpha helixPrion protein PrPSc- glycoprotein with secondary structures dominated by Beta-pleats When PrPSc molecules comes in contact with the normal PrPc molecule the normal PrPc changes into the abnormal PrPSc
Modified protein aggregates in neurons as myeloid plaques
Spongy appearance of cerebrum is due to the formation of vacuoles in the cortex andcerebellum
Spread of PrionsSporadic- no apparent causeInherited - through autosomal dominant traitIngestion - infected food cannibalism
Kuru-incubation ~20 yearsInvolves progressive trunchal shaking and unsteady gait Death within 3-24 months
Medical events- (Iatrogenic) through surgery organs etc
Creutzfeld Jekob Disease (CJD)Most common prion human diseasePeak incidence 55-65 years but can affect teenagersNo treatmentSymptoms
Insidious mental deteriorationEarly cerebellar and visual problemsSevere dementia in 6 monthsBrain and lower motor neuron involvementCases of CJD have been due to
Infected corneal transplantsReused improperly sterilized brain surgery equipment
Pituitary hormone injections derived from cadaversAccidental cuts during autopsies or surgeries
Bovine Variant of CJDBSE re-emerged in 1996 with progressive neurodegenerative disease resulting in patient deathNormally bovine but crossed to humans as Mad Cow DiseaseDiagnosis
Biopsy of BrainSpongiform encephalopathyAccumulation of abnormally folded protein
Sporadic diseaseCSF- no cells
CNS InfectionsThis was by no means a complete inventory of infectious agents involvedThere are many more however we discussed ONLY the very common and frequent infectionsThe original Mad Cow
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Early symptoms (nonspecific)FeverMalaiseAches and painsNauseaVomiting
Headache
HALL MARKS of Meningitis
Symptoms associated with MeningitisDiagnosis of CNS infectionsCerebrospinal Fluid
Chemical and cellular analysisCulturePCR
FEATURES OF CSF
Etiology Leukocytes
(mm3)
Neutrophils
Glucose
(mgdL)
Protein
(mgdL)
Normal 0-6 0 40-80 20-50
Meningitis
Acute Bacterial
gt1000 gt50 0-10 gt100
Viral 10-1000Usually lt300
High for 24hrs then lt50
40-80 50-100
Chronic Mycobact
amp Fungal
100-500 lt10 le40 gt100
(Mycobact)
50-100
(Fungal)
Encephalitis Viral 10-500 High for 24
hrs then lt50
40-80 50-100
BrainAbscess
Bacterial
Fungal
10-100 lt50 40-80 50-100
10-500 RBCs in HHV-1 Infection A Qureshi S2010
Neuroimaging
Helpful in partial differentiation of viral encephalitisJapanese B virus grey matter involvementNipah virus multiple small white matter lesionsHuman herpes virus-1 hemorrhagesAbscesses and Empyema differentiation
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MeningitisInflammation of the meninges occurs due to viral or bacterial infectionsAseptic
Over 50 of the cases are due to a variety of virusesRest of the cases are due to bacteria with special growth requirements or slow growers
CAUSES OF ASEPTIC ASEPTIC ASEPTIC ASEPTIC MENINGITIS
Viruses Bacteria
Common Enteroviruses
Arboviruses
HHV-2
Borrelia burgdorferi
Inadequately treated bacterial
meningitis
Uncommon Mumps
HHV-5 (CMV)
HHV-6
HIV
Mycobacterium tuberculosis
Leptospira sp
Micoplasma pneumoniae
Incidence varies with the region
Modified from Neurol Clin 2008 26635
A Qureshi S10
Viral Infections of CNS
Viruses use at least two pathways to enter the CNSHematogenous (most common)Neural
Through Olfatory nerve- HHV-1amp2Intra-axonal through neuron route- Rabies
Direct injuryViral infections range from meningitis to myelitis
Viral Meningitis Common causes of Aseptic meningitis
Enteroviruses ( ECHO) coxsackie and poliovirusHerpes virus and other viruses are less common
Mumps virus meningitis is a complication of infectionCSF findings
Glucose ndashnormalProtein- moderately highWBC count- increased predominantly lymphocytes
Gram stain- NO BACTERIA
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EnterovirusesEnteroviruses belong to family PicornavirideaNaked small (25-30 nm) icoshedral virusesResistant to pH 3-9 detergents and heatContain single-stranded positive polarity RNA
Transfecting viruses
Baltimore Class IVa RNA replication in cytoplasmMost viruses are CytolyticOver 63 serotypes involved in meningitisPoliovirus has only 3 serotypes and may cause meningitis to myelitisEradicated from the Western Hemisphere through OPV
More than 90 of viral meningitis cases are due to EnterovirusesOther syndromes caused by enteroviruses include
Hand-foot and mouth diseaseHerpanginaMyocarditisPleurodynia
Acute hemorrhagic conjunctivitis
Clinical syndromes are determined byVirus class and serotypeTissue tropismInfectious dosePortal of entryPatient age sex Immune competence
EpidemiologyWorldwide distributionHumans are the only reservoir
Asymptomatic infections are commonShow seasonality
Temperate climates- Summer to Fall (water)Tropical climates- year-round (fecal-oral)Infants and children MOST susceptible
Please refer to Murray et al (6 th Ed)Box 56-4 p 556
PoliovirusesMember of family PicornaviridaeSame viral characters as that of EnterovirusesSpreads through fecal-oral route by consuming contaminated food and waterThrough direct contact with infected stool or throat secretions
Symptoms common to those of meningeal irritationHeadache fever nuchal rigidity followed by weakness in one or more extremities
Clinical syndromeAcute Flaccid Paralysis due to infection of anterior horn of grey matter
PathogenesisInfects enterocytes of the GI tractTransverses intestinal wall through basement membrane
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Moves into gut-associated lymphoid tissue eg Peyerrsquos patches (site of primaryreplication)Resulting viremia seeds peripheral tissue virus enters the neurons of the peripheralnervous system that innervates the peripheral tissues and the virus traffics to the CNSusing retrograde axonal transport
(Lancaster and Pfeiffer 2010)
Outcomes of infectionInapparent infections
95 asymptomatic virus in RESDiagnosis by virus isolation from feces and oropharynx and by specific serumantibodies
Abortive polio (minor illness)- flu like symptomsSimilar to any systemic viral infection
Polio encephalitis- RARENon-paralytic polio (aseptic meningitis)
Similar to other enteroviral meningitis
Paralytic polio (lt2 of cases)Viral spread is normally restricted due to
Limited replication of virus in peripheral neuronsInsufficient retrograde axonal transport in peripheral neuronsInnate resistance through IFN α β production
When these barriers are breeched the out come will be paralytic polioSpinal - flaccid paralysis due lysis of the anterior horn cellsBulbar - paralysis of cranial nerve IX and X medullarrespiratory centers
PreventionInactivated vaccine
Formalized Salk vaccine injected im
Local antibody is not producedMostly used in Western Hemisphere (where polio is considered eradicated)
Please see Table 56-2 in Murray et al 6 th Ed p 561 Live oral vaccine
Sabin vaccine is stable at room temperature with MgCl2Produces secretory antibodiesVirus can spread to contacts and enhance herd immunity and may causeparalytic polio (~1 in 4 million)
Please see Table 56-2 in Murray et al 6 th Ed p 561
Meningitis (Continued)
Septic (as opposed to viral Aseptic) Caused by bacteria onlyAssociated with high Mortality and SeverityEtiology is AGE dependent
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CAUSES OF SEPTIC SEPTIC SEPTIC SEPTIC MENINGITIS
AGE Most common Others
Birth to 3 months Streptococcus agalactiae Escherichia coli L monocytogenes
3 to 60 months Streptococcuspneumoniae
Neisseria meningitidis
H influenzae type b
gt 60 months Streptococcuspneumoniae
Neisseria meningitidis
L monocytogenes
Other Gram negative
organisms
Any age (cranial
surgery)
Staphylococcus aureus
Any age
(immunosuppressed)
L monocytogenes
Other Gram negatives
(including P aeroginosa)
Bacterial Infections of CNSOver 25 infectious agents involvedSevere life threatening infections requiring prompt diagnosis and treatmentSeptic meningitis (Bacterial meningitis)Bacterial invasion into CNS
Invasion from nearby siteMiddle ear or chronic sinusitis
Spread from a distant siteHematogenous invasion
Direct introductionRARE sometimes the source cannot be identified
Bacterial MeningitisNeonates- Strep agalactiae Coliforms and Listeria monocytogenesInfants- Streptococcus pneumoniae Neisseria meningitidis and H influenzaeChildren- Strep pneumoniae N meningitidis and Listeria monocytogenes Streptococcus pneumoniae most common except neonatesMore than 75 of total cases are caused by N meningitidis Strep pneumoniae and Hinfluenzae combined
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CAUSES OF SEPTIC SEPTIC SEPTIC SEPTIC MENINGITIS
AGE Most common Others
Birth to 3 months Streptococcus agalactiae Escherichia coli L monocytogenes
3 to 60 months Streptococcuspneumoniae
Neisseria meningitidis
H influenzae type b
gt 60 months Streptococcuspneumoniae
Neisseria meningitidis
L monocytogenes
Other Gram negative
organisms
Any age (cranial
surgery)
Staphylococcus aureus
Any age
(immunosuppressed)
L monocytogenes
Other Gram negatives
(including P aeroginosa)
Bacterial Virulence FactorsNeisseria meningitidis
Capsule IgA protease pili and endotoxinHaemophilus influenzae
Capsule IgA protease pili and endotoxin Streptococcus pneumoniae
Capsule and IgA protease only
Neisseria meningitidisGram negative coffee bean shaped intracellular (PMNs) exclusively human pathogenMany members of the genus are commensals of upper respiratory tractAbout 30 of the population may transiently carry N meningitidis Responsible for more than 75 cases of septic meningitis ( Reported by Dr Jungkind) Transmission is via droplet inhalationMore than 13 of the cases occur in the first five years of ageHigh morbidity and mortality ~50 survivors have neurologic or other sequelae
DiagnosisClinical signs- rash (Tumbler test) sepsis fever nuchal rigidityCSF tap- protein glucose and WBC count
Culture- fastidious organism requires 5-10 CO2
Blood or CSF sample- plate on chocolate agarNasopharyngeal swab- plate on to Modified Martin-Thayer agar
Contains antibiotics to inhibit normal biotaRapid techniques
Latex agglutinationPCR
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PreventionTetravalent vaccine composed of Groups A C Y and W135 (Group B is weaklyimmunogenic)
Protection is group specificProtection is limited to ~3 yearsVaccination does not protect from carriage of the organism
Vaccine is poorly immunogenic for infants under 2 years of age
Streptococcus agalactiae Beta hemolytic Taxos A resistant Group B streptococcusNormal female genital organism (~40 colonized))60 mortality for babies who develop meningitis during the first week of life
Premature birth is an important risk factorNeonates
Lethargy fever sepsis and respiratory distressChildren and adults
Puerperal fever at delivery and other skin and soft tissue infections
Streptococcus pneumoniaeGram positive lancet shaped alpha hemolytic Taxos P sensitive cocci (Optochin)Part of normal flora of 20 adults and gt75 healthy childrenMOST COMMON cause of bacterial meningitisHighest cause of infantile meningitisMortality rate for pneumococcal meningitis is ~25Neurological sequelae is ~50
In elderly it may follow pneumoniaMiddle ear infectionsSinusiPathogenesis (Braun et al2002 J Clin Invest 10919-27)
Pathogenesis
Hydrogen peroxide- due to absence of catalase large amounts accumulate and enhanceapoptosisPneumolysin
pore forming toxinPotent neurotoxin can trigger cellular apoptosis
Pathogenesis (Guikel et al2003 PNAS10014363-14367)In mouse models invasion can occur through nasopharynx (not hematogenous)Teichoic and lipoteichoic acids of cell wall mediate binding to the gangliosides expressedon the neuronsSubsequent travel is then via retrograde axonal transport along olfactory neurons
Haemophilus influenzae
Gram negative fastidious encapsulated pleomorphic organismsSpread via blood from respiratory tract to the brainInfection opportunity between 4 months to 3 yearsGreater risk of permanent neurologic damage than any other bacterial meningitisVaccines made with type B capsular polysaccharide
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Enterobacteriaceae
Escherichia coli K1Gram negative facultative anaerobesDuring pregnancy increased colonization of K1 strain with 8 mortality
Spreads from nasopharynx to the meningesEnterobacteriaceae Symptoms
lt1 month old- irritability lethargy vomiting lack of appetite and seizures4-18 months- nuchal rigidity tense fontanels and feverOlder children amp adults- headache vomiting confusion lethargy seizures and feve
Interactions during meningitis
Escherichia coli GI respiratory orgenitourinary tract
bloodstream
Slide kindly provided by Dr J Rayner
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Klebsiella pneumoniaeGram negative rodsHigh incidence in cockroach infested areasEarly onset- lt3 days- 2nd only to GBS
(leukopenia and neutropenia)Late onset- 8-28 days-2nd only to Staphylococcus
(leukocytosis and neutrophilia)Symptoms
Lethargy poor feeding little cry fever scleremaCulture from blood CSF urineC-reactive protein positive
Listeria monocytogenesGram positive non spore forming aerobic motile rodsEpidemiology
Food-borne (dairy and deli)Soil water decaying vegetation
Human intestines may be reservoir
2-12 humans carry the organismCan be transmitted to the baby during delivery (may cause spontaneous abortions)Pathogenesis
Grows in macrophagesReleases ldquoInternalinrdquo- as a cell attachment molecule trigger entryListeriolysin- protein that helps in movement within the cellHemolysin- pore-forming toxin Allows escape from phagosome to the phagosoleUses host cell actin to move to the new cells
DiagnosisIntracellular gram positive rods in macrophages and neutrophilsCSF culture- looks like β-Strep but catalase + and ldquotumblerdquo
Slide is kindly provided by Dr Rayner
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Spirochetes Infections of CNSTreponema pallidum
Early stages are infectious and no CNS involvementTakes about 10 year or longer for non treated cases
Neurosyphilis is the Tertiary stage of the disease and no longer infectiousDelayed hypersensitivity is part of the pathologic mechanism of tissue damageCommonly found in different tissues of the body as ldquoGummasrdquoInfection of CNS is via meningovascular routeSpirochetes Infections of CNSSymptoms
CNS degenerative changes resulting in mental changesMay have frank psychosisShuffling gait ldquotabes dorsalisrdquo
DiagnosisSpinal fluid may be helpfulElevated WBCs and protein
VDRL positive
Leptospira interogans Animals are reservoirsSpreads through animal urine contaminated water and food (survives weeks in water)No body of water in the US is free from itSensitive to Acid pH drying and soap~100 casesyearSewer workers miners veterinarians and meat packers are at risk Spirochetes Infections of CNSSymptoms
Incubation 7-13 days (range 5 days - 4 weeks)
Bacteremic phase- influenza like symptoms and fever (bacteria NOW enter the CNS)2 nd Phase - ~3+weeksHeadache with ldquoasepticrdquo meningitisSometimes hemodynamic collapse
DiagnosisBlood cultureCSF analysis and cultureRise in antibody between acute and convalescent stages
Borrelia burgdorferi~15 Neurologic abnormalities rarely fatal
Starts with a tick biteLarge spirochetes- 02x10-30 micromSpirochetes Infections of CNS
SymptomsClassic ldquobullrsquos eyerdquo rash fever joint pain meningeal irritation2nd Stage- dissemination system wide3rd Stage- mild neurologic or frank encephalitis
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DiagnosisLoose irregular spirals Silver or immunoflourescent stainDifficult to cultureCDC recommends antibody screen using ELISA
Fungal Infections of CNSDisseminate hematogenously from a remote site of infection (oropharynx or lung)Create multiple areas of infection within brain and other organsCan cause abscessesMeningoencephalitis occurs early by vascular invasion by fungusCan see secondary thrombosis cerebral infarction and hemorrhages
Common fungiCandida albicansCryptococcus neoformansHistoplasma capsulatumAspergillus fumigatus
DiagnosisAntibody studiesCXRCandida- forms granulomatus reaction Yeast forms seen with silver stainCryptococcus- fungi appear like encapsulated spheres Capsules can be seen bymucicarmine stain Histoplasma- CT scan Aspergillus- branching hyphae classical appearance
Please revisit your notes on Respiratory fungal infections by Dr Lennon
Encephalitis
EtiologyViral
Herpes viruses enteroviruses arboviruses rabies virus HIV HTLV-1Paramyxoviruses (mumps rubeola virus and arenaviruses)
Bacterial (RARE)Exceptions Legionella pneumoniae Borrelia burgdorferi Treponema pallidum
FungalCryptococcus neoformans
ParasiticPlasmodium falciparum Trypanosomes
MyelitisAcute inflammation of the spinal cord
Depending upon virus this can lead to flaccid paralysisSymptoms
HeadacheFeverIrritation followed by
Weakness of one or more extremitiesEtiology
Poliovirus was the leading cause before vaccinationWest Nile virus is the most significant after 2000
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Defined as inflammation of brain parenchymaEncephalitis is considered clinically a more severe syndrome than viral meningitisSymptoms
HeadacheFever
Altered consciousness-lethargy to confusion and comaBehavioral and speech disturbanceSeizures
Arboviruses Arthropod-borne viral infectionsDistributed worldwideTransmitted by mosquitoes and ticksSporadic and epidemic encephalitisSeizures are generally the complications in children
All arboviruses are enveloped viruses with icosahedral nucleocapsid and contain a transfecting RNA
Major families of arboviruses (Togaviridae and Flaviviridae )Togaviridae
Belongs to Baltimore Class IVbEarly and late proteins madeVirus buds at the plasma membrane
TogaviridaeVenezuelan Equine Encephalitis (VEE)Togaviridae (alphavirus)
Spread through Culex and Aedes mosquitoesSymptoms
Prodrome- fever chills weakness headache myalgia (due to viral replication )Rapid progression- nuchal rigidity confusion somnolence seizure in 50 of cases andcoma (due to spread through microvascular permeability of brain then cell-to-celloccurs via axon and dendrites )NO DEATHS in humans 80 mortality in horses
Eastern Equine Encephalitis (EEE)Common in North AmericaSpreads through Aedes and Culiseta spHumans are dead-end hosts but Aedes may spread from horse to human
Clinical symptoms similar to that of VEEHIGH MORTALITY in humans
Western Equine Encephalitis (WEE)Spreads through Culex and CulisetaCommon in rural areas of US in summer monthsFatality rate 3-4 death in 1-2 days Children have a 30 chance of CNS sequelae
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Pathophysiology of Equine EncephalitidesDefuse CNS involvementNeutrophils and macrophages infiltrate brain parenchyma causing focal necrosis and spottydemyelinationVascular inflammation with endothelial proliferation and small vessel thrombosis
EEELarge number of active virus entering in brain parenchymaEffects the perikaryon and dendrites of neurons with minimal glial cell infiltration
WEEDamage mediated by large number of immunologically active cells that enterbrainCell death by apoptosis primarily in the glial and inflammatory cells
FlaviviridaeBelongs to Baltimore class IVaPolyprotein is translated first which cleaves into many individual proteinsVirus buds inside cytoplasmic vesicles and the virus is released through
exocytosis
St Louis Encephalitis virus (SLE)Epidemiology
Transmitted by culex mosquitoesOvert infection depends upon
Efficiency of replication at extra neural sitesDegree of viremiaAge of the host
PathophysiologyVirus enters through BBB (astrocyte complex)
Or cross fenestrated endothelium (choroid plexus)Symptoms
Mortality 2-20 (higher in elderly)Malaise and fever only 20 develop sequelae (irritability memory loss movementdisorders motor deficits)Seizures and coma COMMONNo chronic illness
Japanese B Encephalitis virus (JBE)Epidemiology
Spread through Culex mosquitoesIncubation 4-14 days
Rural areas of AsiaSeptember 2010 India 319 deaths and Nepal 5 deaths
SymptomsViral prodrome- fever by 2nd weekEncephalitis syndrome with tremors NOT seizuresLow CSF IgGIgM ratio= higher death rate
West Nile Encephalitis virus (WNV)Epidemiology
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Wild birds are reservoir spreads through Aedes mosquitoes3-15 fatalVery RARE person to person transmission
SymptomsViral prodrome with maculopapular rash on trunk and extremitiesHeadache HIGH fever nuchal rigidity stupor tremor and seizures paralysis
BunyaviridaeAt least 200 different viruses included in this groupEnveloped viruses containing single-stranded negative polarity segmented (3) RNASpreads through mosquitoes ticks and flies
California Encephalitis virusLa Crosse virus
RhabdoviridaeLyssavirus RabiesStructure
Bullet shaped virusSingle-stranded negative polarity RNA
Helical nucleocapsid in an envelope5 proteins- NPMG and L
Surface glycoprotein attaches to cell receptors including Acetylcholine receptor atneuromuscular junctions
PathophysiologyViral entry into the cell is via endocytosisVirus has a preference for nerve and salivary gland cells (travels via axons to CNS)Spreads from brain to salivary glands kidneys and conjunctival cells (virus in tears )
EpidemiologyEstimated 35000-50000 cases worldwide
Highest in Asia ~90 casesEndozoonotic all warm blooded animals are susceptible
Urban- dogs and catsSylvatic- wildlife
SymptomsIncubation 20-90 days may extend to a yearNonspecific ndash general malaise fever headache (tingling pain and weakness at the bitsite)Progressive - neurologic symptoms including insomnia confusion slight or partialparalysis agitation hypersalivation dysphagia (hydrophobia)Paralytic ndashdisorientation stupor
Death within days after symptoms (~7 days)Diagnosis
Saliva- virus isolation RT-PCRSerum and CSF for rabies antibodies (FA and ELISA)Brain tissue- Negri bodies Babes nodules consisting of glial cells
TreatmentPrevention
Wash all wounds with soap and water
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1 dose of immune globulin and 4 doses of vaccine on days 137 amp14 days + 2boosters on days 0 and 3
New recommendations by CDC published on Mar 18 2010
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010(MMWR VOL59RR2 MAR 18 2010)
NOT PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent (eg povidine-iodinesolution) should be used to irrigate the wounds
Human rabies
immune globulin(HRIG)
Administer 20 IUkg body weight If anatomicallyfeasible the full dose should be infiltrated around and
into the wound(s) and any remaining volume shouldbe administered at an anatomical site (intramuscular
[IM]) distant from vaccine administration
Vaccine Human diploid cell vaccine (HDCV) or purified chickembryo cell vaccine (PCECV) 10 mL IM (deltoid but
never in the gluteal region) 1 each on days 0 3 7 and
14(For immunocompromised 5 shots)
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010
(MMWR VOL59RR2 MAR 18 2010)
PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent such as povidine-iodinesolution should be used to irrigate the wounds
HRIG HRIG should not be administered
Vaccine HDCV or PCECV 10 mL IM (deltoid but never in the
gluteal area) 1 each on days 0 and 3
For persons with immunosuppression rabies PEPshould be administered using all 5 doses of vaccine on
days 0 3 7 14 and 28
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Other virus infections of the CNSArenaviridae - Lymphocytic ChoriomeningitisTogaviridae- Rubella virusHerpesviridae - Human Herpes virus 1-8Retroviridae - HIV-1Other virus infections of the CNS
Papovaviridae - Polyoma virus (JC virus)-PML (Progressive Multifocal Leukoencephalopathy)Viral DNA in majority of healthy humansMultifocal signs including hemiparesis visual loss seizures dementia personalitychanges and gait problemsCharacteristic white matter lesions common in posterior occipital area
Paramyxoviridae - Mumps viruses and Measles- SSPE (Subacute Sclerosing Pan Encephalitis)Slow fatal condition after more than 10 years of measlesWorldwide more common in boys (31) than girlsBehavior changes in school age childrenFulminant course- 10 of cases death in 3 monthsChronic course- death in 4-10 years
Brain Abscess and EmpyemaLocalized bacterial infection of brain parenchyma and subdural or epidural spacesPressure from accumulation of exudates may permanently damage the brain tissueMay be fatal if not treated properlyAbscess
Fixed boundariesEmpyema
Lack of definable shape or sizeBrain Abscess
Symptoms
Usually are rapid and associated with their locationHeadacheChanges in mental status- drowsiness to comaGeneralized seizure
Fungal brain abscessDisseminated hematogenously from remote site ( lungs or oropharynx)Create multiple areas of infection within brainMeningoencephalitis occurs early by vascular invasionEtiology
Aspergillus Cryptococcus Candida
Transmissible Spongiform EncephalopathiesPrion is an abnormal isomer of normal host proteinNO NUCLEIC ACID presentReplicate without provoking antibody or inflammatory responseAre resistant to some inactivation methods used for bacteria and viruses (70 alcohol X-raysand UV light etc)Sensitive to autoclaving and bleachDisease confined to the CNS and may take decades to manifestCan be inherited (~15) of cases)
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PathogenesisNormal PrPc- glycoprotein with secondary structures dominated by Alpha helixPrion protein PrPSc- glycoprotein with secondary structures dominated by Beta-pleats When PrPSc molecules comes in contact with the normal PrPc molecule the normal PrPc changes into the abnormal PrPSc
Modified protein aggregates in neurons as myeloid plaques
Spongy appearance of cerebrum is due to the formation of vacuoles in the cortex andcerebellum
Spread of PrionsSporadic- no apparent causeInherited - through autosomal dominant traitIngestion - infected food cannibalism
Kuru-incubation ~20 yearsInvolves progressive trunchal shaking and unsteady gait Death within 3-24 months
Medical events- (Iatrogenic) through surgery organs etc
Creutzfeld Jekob Disease (CJD)Most common prion human diseasePeak incidence 55-65 years but can affect teenagersNo treatmentSymptoms
Insidious mental deteriorationEarly cerebellar and visual problemsSevere dementia in 6 monthsBrain and lower motor neuron involvementCases of CJD have been due to
Infected corneal transplantsReused improperly sterilized brain surgery equipment
Pituitary hormone injections derived from cadaversAccidental cuts during autopsies or surgeries
Bovine Variant of CJDBSE re-emerged in 1996 with progressive neurodegenerative disease resulting in patient deathNormally bovine but crossed to humans as Mad Cow DiseaseDiagnosis
Biopsy of BrainSpongiform encephalopathyAccumulation of abnormally folded protein
Sporadic diseaseCSF- no cells
CNS InfectionsThis was by no means a complete inventory of infectious agents involvedThere are many more however we discussed ONLY the very common and frequent infectionsThe original Mad Cow
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MeningitisInflammation of the meninges occurs due to viral or bacterial infectionsAseptic
Over 50 of the cases are due to a variety of virusesRest of the cases are due to bacteria with special growth requirements or slow growers
CAUSES OF ASEPTIC ASEPTIC ASEPTIC ASEPTIC MENINGITIS
Viruses Bacteria
Common Enteroviruses
Arboviruses
HHV-2
Borrelia burgdorferi
Inadequately treated bacterial
meningitis
Uncommon Mumps
HHV-5 (CMV)
HHV-6
HIV
Mycobacterium tuberculosis
Leptospira sp
Micoplasma pneumoniae
Incidence varies with the region
Modified from Neurol Clin 2008 26635
A Qureshi S10
Viral Infections of CNS
Viruses use at least two pathways to enter the CNSHematogenous (most common)Neural
Through Olfatory nerve- HHV-1amp2Intra-axonal through neuron route- Rabies
Direct injuryViral infections range from meningitis to myelitis
Viral Meningitis Common causes of Aseptic meningitis
Enteroviruses ( ECHO) coxsackie and poliovirusHerpes virus and other viruses are less common
Mumps virus meningitis is a complication of infectionCSF findings
Glucose ndashnormalProtein- moderately highWBC count- increased predominantly lymphocytes
Gram stain- NO BACTERIA
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EnterovirusesEnteroviruses belong to family PicornavirideaNaked small (25-30 nm) icoshedral virusesResistant to pH 3-9 detergents and heatContain single-stranded positive polarity RNA
Transfecting viruses
Baltimore Class IVa RNA replication in cytoplasmMost viruses are CytolyticOver 63 serotypes involved in meningitisPoliovirus has only 3 serotypes and may cause meningitis to myelitisEradicated from the Western Hemisphere through OPV
More than 90 of viral meningitis cases are due to EnterovirusesOther syndromes caused by enteroviruses include
Hand-foot and mouth diseaseHerpanginaMyocarditisPleurodynia
Acute hemorrhagic conjunctivitis
Clinical syndromes are determined byVirus class and serotypeTissue tropismInfectious dosePortal of entryPatient age sex Immune competence
EpidemiologyWorldwide distributionHumans are the only reservoir
Asymptomatic infections are commonShow seasonality
Temperate climates- Summer to Fall (water)Tropical climates- year-round (fecal-oral)Infants and children MOST susceptible
Please refer to Murray et al (6 th Ed)Box 56-4 p 556
PoliovirusesMember of family PicornaviridaeSame viral characters as that of EnterovirusesSpreads through fecal-oral route by consuming contaminated food and waterThrough direct contact with infected stool or throat secretions
Symptoms common to those of meningeal irritationHeadache fever nuchal rigidity followed by weakness in one or more extremities
Clinical syndromeAcute Flaccid Paralysis due to infection of anterior horn of grey matter
PathogenesisInfects enterocytes of the GI tractTransverses intestinal wall through basement membrane
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Moves into gut-associated lymphoid tissue eg Peyerrsquos patches (site of primaryreplication)Resulting viremia seeds peripheral tissue virus enters the neurons of the peripheralnervous system that innervates the peripheral tissues and the virus traffics to the CNSusing retrograde axonal transport
(Lancaster and Pfeiffer 2010)
Outcomes of infectionInapparent infections
95 asymptomatic virus in RESDiagnosis by virus isolation from feces and oropharynx and by specific serumantibodies
Abortive polio (minor illness)- flu like symptomsSimilar to any systemic viral infection
Polio encephalitis- RARENon-paralytic polio (aseptic meningitis)
Similar to other enteroviral meningitis
Paralytic polio (lt2 of cases)Viral spread is normally restricted due to
Limited replication of virus in peripheral neuronsInsufficient retrograde axonal transport in peripheral neuronsInnate resistance through IFN α β production
When these barriers are breeched the out come will be paralytic polioSpinal - flaccid paralysis due lysis of the anterior horn cellsBulbar - paralysis of cranial nerve IX and X medullarrespiratory centers
PreventionInactivated vaccine
Formalized Salk vaccine injected im
Local antibody is not producedMostly used in Western Hemisphere (where polio is considered eradicated)
Please see Table 56-2 in Murray et al 6 th Ed p 561 Live oral vaccine
Sabin vaccine is stable at room temperature with MgCl2Produces secretory antibodiesVirus can spread to contacts and enhance herd immunity and may causeparalytic polio (~1 in 4 million)
Please see Table 56-2 in Murray et al 6 th Ed p 561
Meningitis (Continued)
Septic (as opposed to viral Aseptic) Caused by bacteria onlyAssociated with high Mortality and SeverityEtiology is AGE dependent
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CAUSES OF SEPTIC SEPTIC SEPTIC SEPTIC MENINGITIS
AGE Most common Others
Birth to 3 months Streptococcus agalactiae Escherichia coli L monocytogenes
3 to 60 months Streptococcuspneumoniae
Neisseria meningitidis
H influenzae type b
gt 60 months Streptococcuspneumoniae
Neisseria meningitidis
L monocytogenes
Other Gram negative
organisms
Any age (cranial
surgery)
Staphylococcus aureus
Any age
(immunosuppressed)
L monocytogenes
Other Gram negatives
(including P aeroginosa)
Bacterial Infections of CNSOver 25 infectious agents involvedSevere life threatening infections requiring prompt diagnosis and treatmentSeptic meningitis (Bacterial meningitis)Bacterial invasion into CNS
Invasion from nearby siteMiddle ear or chronic sinusitis
Spread from a distant siteHematogenous invasion
Direct introductionRARE sometimes the source cannot be identified
Bacterial MeningitisNeonates- Strep agalactiae Coliforms and Listeria monocytogenesInfants- Streptococcus pneumoniae Neisseria meningitidis and H influenzaeChildren- Strep pneumoniae N meningitidis and Listeria monocytogenes Streptococcus pneumoniae most common except neonatesMore than 75 of total cases are caused by N meningitidis Strep pneumoniae and Hinfluenzae combined
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CAUSES OF SEPTIC SEPTIC SEPTIC SEPTIC MENINGITIS
AGE Most common Others
Birth to 3 months Streptococcus agalactiae Escherichia coli L monocytogenes
3 to 60 months Streptococcuspneumoniae
Neisseria meningitidis
H influenzae type b
gt 60 months Streptococcuspneumoniae
Neisseria meningitidis
L monocytogenes
Other Gram negative
organisms
Any age (cranial
surgery)
Staphylococcus aureus
Any age
(immunosuppressed)
L monocytogenes
Other Gram negatives
(including P aeroginosa)
Bacterial Virulence FactorsNeisseria meningitidis
Capsule IgA protease pili and endotoxinHaemophilus influenzae
Capsule IgA protease pili and endotoxin Streptococcus pneumoniae
Capsule and IgA protease only
Neisseria meningitidisGram negative coffee bean shaped intracellular (PMNs) exclusively human pathogenMany members of the genus are commensals of upper respiratory tractAbout 30 of the population may transiently carry N meningitidis Responsible for more than 75 cases of septic meningitis ( Reported by Dr Jungkind) Transmission is via droplet inhalationMore than 13 of the cases occur in the first five years of ageHigh morbidity and mortality ~50 survivors have neurologic or other sequelae
DiagnosisClinical signs- rash (Tumbler test) sepsis fever nuchal rigidityCSF tap- protein glucose and WBC count
Culture- fastidious organism requires 5-10 CO2
Blood or CSF sample- plate on chocolate agarNasopharyngeal swab- plate on to Modified Martin-Thayer agar
Contains antibiotics to inhibit normal biotaRapid techniques
Latex agglutinationPCR
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PreventionTetravalent vaccine composed of Groups A C Y and W135 (Group B is weaklyimmunogenic)
Protection is group specificProtection is limited to ~3 yearsVaccination does not protect from carriage of the organism
Vaccine is poorly immunogenic for infants under 2 years of age
Streptococcus agalactiae Beta hemolytic Taxos A resistant Group B streptococcusNormal female genital organism (~40 colonized))60 mortality for babies who develop meningitis during the first week of life
Premature birth is an important risk factorNeonates
Lethargy fever sepsis and respiratory distressChildren and adults
Puerperal fever at delivery and other skin and soft tissue infections
Streptococcus pneumoniaeGram positive lancet shaped alpha hemolytic Taxos P sensitive cocci (Optochin)Part of normal flora of 20 adults and gt75 healthy childrenMOST COMMON cause of bacterial meningitisHighest cause of infantile meningitisMortality rate for pneumococcal meningitis is ~25Neurological sequelae is ~50
In elderly it may follow pneumoniaMiddle ear infectionsSinusiPathogenesis (Braun et al2002 J Clin Invest 10919-27)
Pathogenesis
Hydrogen peroxide- due to absence of catalase large amounts accumulate and enhanceapoptosisPneumolysin
pore forming toxinPotent neurotoxin can trigger cellular apoptosis
Pathogenesis (Guikel et al2003 PNAS10014363-14367)In mouse models invasion can occur through nasopharynx (not hematogenous)Teichoic and lipoteichoic acids of cell wall mediate binding to the gangliosides expressedon the neuronsSubsequent travel is then via retrograde axonal transport along olfactory neurons
Haemophilus influenzae
Gram negative fastidious encapsulated pleomorphic organismsSpread via blood from respiratory tract to the brainInfection opportunity between 4 months to 3 yearsGreater risk of permanent neurologic damage than any other bacterial meningitisVaccines made with type B capsular polysaccharide
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Enterobacteriaceae
Escherichia coli K1Gram negative facultative anaerobesDuring pregnancy increased colonization of K1 strain with 8 mortality
Spreads from nasopharynx to the meningesEnterobacteriaceae Symptoms
lt1 month old- irritability lethargy vomiting lack of appetite and seizures4-18 months- nuchal rigidity tense fontanels and feverOlder children amp adults- headache vomiting confusion lethargy seizures and feve
Interactions during meningitis
Escherichia coli GI respiratory orgenitourinary tract
bloodstream
Slide kindly provided by Dr J Rayner
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Klebsiella pneumoniaeGram negative rodsHigh incidence in cockroach infested areasEarly onset- lt3 days- 2nd only to GBS
(leukopenia and neutropenia)Late onset- 8-28 days-2nd only to Staphylococcus
(leukocytosis and neutrophilia)Symptoms
Lethargy poor feeding little cry fever scleremaCulture from blood CSF urineC-reactive protein positive
Listeria monocytogenesGram positive non spore forming aerobic motile rodsEpidemiology
Food-borne (dairy and deli)Soil water decaying vegetation
Human intestines may be reservoir
2-12 humans carry the organismCan be transmitted to the baby during delivery (may cause spontaneous abortions)Pathogenesis
Grows in macrophagesReleases ldquoInternalinrdquo- as a cell attachment molecule trigger entryListeriolysin- protein that helps in movement within the cellHemolysin- pore-forming toxin Allows escape from phagosome to the phagosoleUses host cell actin to move to the new cells
DiagnosisIntracellular gram positive rods in macrophages and neutrophilsCSF culture- looks like β-Strep but catalase + and ldquotumblerdquo
Slide is kindly provided by Dr Rayner
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Spirochetes Infections of CNSTreponema pallidum
Early stages are infectious and no CNS involvementTakes about 10 year or longer for non treated cases
Neurosyphilis is the Tertiary stage of the disease and no longer infectiousDelayed hypersensitivity is part of the pathologic mechanism of tissue damageCommonly found in different tissues of the body as ldquoGummasrdquoInfection of CNS is via meningovascular routeSpirochetes Infections of CNSSymptoms
CNS degenerative changes resulting in mental changesMay have frank psychosisShuffling gait ldquotabes dorsalisrdquo
DiagnosisSpinal fluid may be helpfulElevated WBCs and protein
VDRL positive
Leptospira interogans Animals are reservoirsSpreads through animal urine contaminated water and food (survives weeks in water)No body of water in the US is free from itSensitive to Acid pH drying and soap~100 casesyearSewer workers miners veterinarians and meat packers are at risk Spirochetes Infections of CNSSymptoms
Incubation 7-13 days (range 5 days - 4 weeks)
Bacteremic phase- influenza like symptoms and fever (bacteria NOW enter the CNS)2 nd Phase - ~3+weeksHeadache with ldquoasepticrdquo meningitisSometimes hemodynamic collapse
DiagnosisBlood cultureCSF analysis and cultureRise in antibody between acute and convalescent stages
Borrelia burgdorferi~15 Neurologic abnormalities rarely fatal
Starts with a tick biteLarge spirochetes- 02x10-30 micromSpirochetes Infections of CNS
SymptomsClassic ldquobullrsquos eyerdquo rash fever joint pain meningeal irritation2nd Stage- dissemination system wide3rd Stage- mild neurologic or frank encephalitis
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DiagnosisLoose irregular spirals Silver or immunoflourescent stainDifficult to cultureCDC recommends antibody screen using ELISA
Fungal Infections of CNSDisseminate hematogenously from a remote site of infection (oropharynx or lung)Create multiple areas of infection within brain and other organsCan cause abscessesMeningoencephalitis occurs early by vascular invasion by fungusCan see secondary thrombosis cerebral infarction and hemorrhages
Common fungiCandida albicansCryptococcus neoformansHistoplasma capsulatumAspergillus fumigatus
DiagnosisAntibody studiesCXRCandida- forms granulomatus reaction Yeast forms seen with silver stainCryptococcus- fungi appear like encapsulated spheres Capsules can be seen bymucicarmine stain Histoplasma- CT scan Aspergillus- branching hyphae classical appearance
Please revisit your notes on Respiratory fungal infections by Dr Lennon
Encephalitis
EtiologyViral
Herpes viruses enteroviruses arboviruses rabies virus HIV HTLV-1Paramyxoviruses (mumps rubeola virus and arenaviruses)
Bacterial (RARE)Exceptions Legionella pneumoniae Borrelia burgdorferi Treponema pallidum
FungalCryptococcus neoformans
ParasiticPlasmodium falciparum Trypanosomes
MyelitisAcute inflammation of the spinal cord
Depending upon virus this can lead to flaccid paralysisSymptoms
HeadacheFeverIrritation followed by
Weakness of one or more extremitiesEtiology
Poliovirus was the leading cause before vaccinationWest Nile virus is the most significant after 2000
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Defined as inflammation of brain parenchymaEncephalitis is considered clinically a more severe syndrome than viral meningitisSymptoms
HeadacheFever
Altered consciousness-lethargy to confusion and comaBehavioral and speech disturbanceSeizures
Arboviruses Arthropod-borne viral infectionsDistributed worldwideTransmitted by mosquitoes and ticksSporadic and epidemic encephalitisSeizures are generally the complications in children
All arboviruses are enveloped viruses with icosahedral nucleocapsid and contain a transfecting RNA
Major families of arboviruses (Togaviridae and Flaviviridae )Togaviridae
Belongs to Baltimore Class IVbEarly and late proteins madeVirus buds at the plasma membrane
TogaviridaeVenezuelan Equine Encephalitis (VEE)Togaviridae (alphavirus)
Spread through Culex and Aedes mosquitoesSymptoms
Prodrome- fever chills weakness headache myalgia (due to viral replication )Rapid progression- nuchal rigidity confusion somnolence seizure in 50 of cases andcoma (due to spread through microvascular permeability of brain then cell-to-celloccurs via axon and dendrites )NO DEATHS in humans 80 mortality in horses
Eastern Equine Encephalitis (EEE)Common in North AmericaSpreads through Aedes and Culiseta spHumans are dead-end hosts but Aedes may spread from horse to human
Clinical symptoms similar to that of VEEHIGH MORTALITY in humans
Western Equine Encephalitis (WEE)Spreads through Culex and CulisetaCommon in rural areas of US in summer monthsFatality rate 3-4 death in 1-2 days Children have a 30 chance of CNS sequelae
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Pathophysiology of Equine EncephalitidesDefuse CNS involvementNeutrophils and macrophages infiltrate brain parenchyma causing focal necrosis and spottydemyelinationVascular inflammation with endothelial proliferation and small vessel thrombosis
EEELarge number of active virus entering in brain parenchymaEffects the perikaryon and dendrites of neurons with minimal glial cell infiltration
WEEDamage mediated by large number of immunologically active cells that enterbrainCell death by apoptosis primarily in the glial and inflammatory cells
FlaviviridaeBelongs to Baltimore class IVaPolyprotein is translated first which cleaves into many individual proteinsVirus buds inside cytoplasmic vesicles and the virus is released through
exocytosis
St Louis Encephalitis virus (SLE)Epidemiology
Transmitted by culex mosquitoesOvert infection depends upon
Efficiency of replication at extra neural sitesDegree of viremiaAge of the host
PathophysiologyVirus enters through BBB (astrocyte complex)
Or cross fenestrated endothelium (choroid plexus)Symptoms
Mortality 2-20 (higher in elderly)Malaise and fever only 20 develop sequelae (irritability memory loss movementdisorders motor deficits)Seizures and coma COMMONNo chronic illness
Japanese B Encephalitis virus (JBE)Epidemiology
Spread through Culex mosquitoesIncubation 4-14 days
Rural areas of AsiaSeptember 2010 India 319 deaths and Nepal 5 deaths
SymptomsViral prodrome- fever by 2nd weekEncephalitis syndrome with tremors NOT seizuresLow CSF IgGIgM ratio= higher death rate
West Nile Encephalitis virus (WNV)Epidemiology
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Wild birds are reservoir spreads through Aedes mosquitoes3-15 fatalVery RARE person to person transmission
SymptomsViral prodrome with maculopapular rash on trunk and extremitiesHeadache HIGH fever nuchal rigidity stupor tremor and seizures paralysis
BunyaviridaeAt least 200 different viruses included in this groupEnveloped viruses containing single-stranded negative polarity segmented (3) RNASpreads through mosquitoes ticks and flies
California Encephalitis virusLa Crosse virus
RhabdoviridaeLyssavirus RabiesStructure
Bullet shaped virusSingle-stranded negative polarity RNA
Helical nucleocapsid in an envelope5 proteins- NPMG and L
Surface glycoprotein attaches to cell receptors including Acetylcholine receptor atneuromuscular junctions
PathophysiologyViral entry into the cell is via endocytosisVirus has a preference for nerve and salivary gland cells (travels via axons to CNS)Spreads from brain to salivary glands kidneys and conjunctival cells (virus in tears )
EpidemiologyEstimated 35000-50000 cases worldwide
Highest in Asia ~90 casesEndozoonotic all warm blooded animals are susceptible
Urban- dogs and catsSylvatic- wildlife
SymptomsIncubation 20-90 days may extend to a yearNonspecific ndash general malaise fever headache (tingling pain and weakness at the bitsite)Progressive - neurologic symptoms including insomnia confusion slight or partialparalysis agitation hypersalivation dysphagia (hydrophobia)Paralytic ndashdisorientation stupor
Death within days after symptoms (~7 days)Diagnosis
Saliva- virus isolation RT-PCRSerum and CSF for rabies antibodies (FA and ELISA)Brain tissue- Negri bodies Babes nodules consisting of glial cells
TreatmentPrevention
Wash all wounds with soap and water
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1 dose of immune globulin and 4 doses of vaccine on days 137 amp14 days + 2boosters on days 0 and 3
New recommendations by CDC published on Mar 18 2010
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010(MMWR VOL59RR2 MAR 18 2010)
NOT PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent (eg povidine-iodinesolution) should be used to irrigate the wounds
Human rabies
immune globulin(HRIG)
Administer 20 IUkg body weight If anatomicallyfeasible the full dose should be infiltrated around and
into the wound(s) and any remaining volume shouldbe administered at an anatomical site (intramuscular
[IM]) distant from vaccine administration
Vaccine Human diploid cell vaccine (HDCV) or purified chickembryo cell vaccine (PCECV) 10 mL IM (deltoid but
never in the gluteal region) 1 each on days 0 3 7 and
14(For immunocompromised 5 shots)
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010
(MMWR VOL59RR2 MAR 18 2010)
PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent such as povidine-iodinesolution should be used to irrigate the wounds
HRIG HRIG should not be administered
Vaccine HDCV or PCECV 10 mL IM (deltoid but never in the
gluteal area) 1 each on days 0 and 3
For persons with immunosuppression rabies PEPshould be administered using all 5 doses of vaccine on
days 0 3 7 14 and 28
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Other virus infections of the CNSArenaviridae - Lymphocytic ChoriomeningitisTogaviridae- Rubella virusHerpesviridae - Human Herpes virus 1-8Retroviridae - HIV-1Other virus infections of the CNS
Papovaviridae - Polyoma virus (JC virus)-PML (Progressive Multifocal Leukoencephalopathy)Viral DNA in majority of healthy humansMultifocal signs including hemiparesis visual loss seizures dementia personalitychanges and gait problemsCharacteristic white matter lesions common in posterior occipital area
Paramyxoviridae - Mumps viruses and Measles- SSPE (Subacute Sclerosing Pan Encephalitis)Slow fatal condition after more than 10 years of measlesWorldwide more common in boys (31) than girlsBehavior changes in school age childrenFulminant course- 10 of cases death in 3 monthsChronic course- death in 4-10 years
Brain Abscess and EmpyemaLocalized bacterial infection of brain parenchyma and subdural or epidural spacesPressure from accumulation of exudates may permanently damage the brain tissueMay be fatal if not treated properlyAbscess
Fixed boundariesEmpyema
Lack of definable shape or sizeBrain Abscess
Symptoms
Usually are rapid and associated with their locationHeadacheChanges in mental status- drowsiness to comaGeneralized seizure
Fungal brain abscessDisseminated hematogenously from remote site ( lungs or oropharynx)Create multiple areas of infection within brainMeningoencephalitis occurs early by vascular invasionEtiology
Aspergillus Cryptococcus Candida
Transmissible Spongiform EncephalopathiesPrion is an abnormal isomer of normal host proteinNO NUCLEIC ACID presentReplicate without provoking antibody or inflammatory responseAre resistant to some inactivation methods used for bacteria and viruses (70 alcohol X-raysand UV light etc)Sensitive to autoclaving and bleachDisease confined to the CNS and may take decades to manifestCan be inherited (~15) of cases)
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PathogenesisNormal PrPc- glycoprotein with secondary structures dominated by Alpha helixPrion protein PrPSc- glycoprotein with secondary structures dominated by Beta-pleats When PrPSc molecules comes in contact with the normal PrPc molecule the normal PrPc changes into the abnormal PrPSc
Modified protein aggregates in neurons as myeloid plaques
Spongy appearance of cerebrum is due to the formation of vacuoles in the cortex andcerebellum
Spread of PrionsSporadic- no apparent causeInherited - through autosomal dominant traitIngestion - infected food cannibalism
Kuru-incubation ~20 yearsInvolves progressive trunchal shaking and unsteady gait Death within 3-24 months
Medical events- (Iatrogenic) through surgery organs etc
Creutzfeld Jekob Disease (CJD)Most common prion human diseasePeak incidence 55-65 years but can affect teenagersNo treatmentSymptoms
Insidious mental deteriorationEarly cerebellar and visual problemsSevere dementia in 6 monthsBrain and lower motor neuron involvementCases of CJD have been due to
Infected corneal transplantsReused improperly sterilized brain surgery equipment
Pituitary hormone injections derived from cadaversAccidental cuts during autopsies or surgeries
Bovine Variant of CJDBSE re-emerged in 1996 with progressive neurodegenerative disease resulting in patient deathNormally bovine but crossed to humans as Mad Cow DiseaseDiagnosis
Biopsy of BrainSpongiform encephalopathyAccumulation of abnormally folded protein
Sporadic diseaseCSF- no cells
CNS InfectionsThis was by no means a complete inventory of infectious agents involvedThere are many more however we discussed ONLY the very common and frequent infectionsThe original Mad Cow
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EnterovirusesEnteroviruses belong to family PicornavirideaNaked small (25-30 nm) icoshedral virusesResistant to pH 3-9 detergents and heatContain single-stranded positive polarity RNA
Transfecting viruses
Baltimore Class IVa RNA replication in cytoplasmMost viruses are CytolyticOver 63 serotypes involved in meningitisPoliovirus has only 3 serotypes and may cause meningitis to myelitisEradicated from the Western Hemisphere through OPV
More than 90 of viral meningitis cases are due to EnterovirusesOther syndromes caused by enteroviruses include
Hand-foot and mouth diseaseHerpanginaMyocarditisPleurodynia
Acute hemorrhagic conjunctivitis
Clinical syndromes are determined byVirus class and serotypeTissue tropismInfectious dosePortal of entryPatient age sex Immune competence
EpidemiologyWorldwide distributionHumans are the only reservoir
Asymptomatic infections are commonShow seasonality
Temperate climates- Summer to Fall (water)Tropical climates- year-round (fecal-oral)Infants and children MOST susceptible
Please refer to Murray et al (6 th Ed)Box 56-4 p 556
PoliovirusesMember of family PicornaviridaeSame viral characters as that of EnterovirusesSpreads through fecal-oral route by consuming contaminated food and waterThrough direct contact with infected stool or throat secretions
Symptoms common to those of meningeal irritationHeadache fever nuchal rigidity followed by weakness in one or more extremities
Clinical syndromeAcute Flaccid Paralysis due to infection of anterior horn of grey matter
PathogenesisInfects enterocytes of the GI tractTransverses intestinal wall through basement membrane
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Moves into gut-associated lymphoid tissue eg Peyerrsquos patches (site of primaryreplication)Resulting viremia seeds peripheral tissue virus enters the neurons of the peripheralnervous system that innervates the peripheral tissues and the virus traffics to the CNSusing retrograde axonal transport
(Lancaster and Pfeiffer 2010)
Outcomes of infectionInapparent infections
95 asymptomatic virus in RESDiagnosis by virus isolation from feces and oropharynx and by specific serumantibodies
Abortive polio (minor illness)- flu like symptomsSimilar to any systemic viral infection
Polio encephalitis- RARENon-paralytic polio (aseptic meningitis)
Similar to other enteroviral meningitis
Paralytic polio (lt2 of cases)Viral spread is normally restricted due to
Limited replication of virus in peripheral neuronsInsufficient retrograde axonal transport in peripheral neuronsInnate resistance through IFN α β production
When these barriers are breeched the out come will be paralytic polioSpinal - flaccid paralysis due lysis of the anterior horn cellsBulbar - paralysis of cranial nerve IX and X medullarrespiratory centers
PreventionInactivated vaccine
Formalized Salk vaccine injected im
Local antibody is not producedMostly used in Western Hemisphere (where polio is considered eradicated)
Please see Table 56-2 in Murray et al 6 th Ed p 561 Live oral vaccine
Sabin vaccine is stable at room temperature with MgCl2Produces secretory antibodiesVirus can spread to contacts and enhance herd immunity and may causeparalytic polio (~1 in 4 million)
Please see Table 56-2 in Murray et al 6 th Ed p 561
Meningitis (Continued)
Septic (as opposed to viral Aseptic) Caused by bacteria onlyAssociated with high Mortality and SeverityEtiology is AGE dependent
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CAUSES OF SEPTIC SEPTIC SEPTIC SEPTIC MENINGITIS
AGE Most common Others
Birth to 3 months Streptococcus agalactiae Escherichia coli L monocytogenes
3 to 60 months Streptococcuspneumoniae
Neisseria meningitidis
H influenzae type b
gt 60 months Streptococcuspneumoniae
Neisseria meningitidis
L monocytogenes
Other Gram negative
organisms
Any age (cranial
surgery)
Staphylococcus aureus
Any age
(immunosuppressed)
L monocytogenes
Other Gram negatives
(including P aeroginosa)
Bacterial Infections of CNSOver 25 infectious agents involvedSevere life threatening infections requiring prompt diagnosis and treatmentSeptic meningitis (Bacterial meningitis)Bacterial invasion into CNS
Invasion from nearby siteMiddle ear or chronic sinusitis
Spread from a distant siteHematogenous invasion
Direct introductionRARE sometimes the source cannot be identified
Bacterial MeningitisNeonates- Strep agalactiae Coliforms and Listeria monocytogenesInfants- Streptococcus pneumoniae Neisseria meningitidis and H influenzaeChildren- Strep pneumoniae N meningitidis and Listeria monocytogenes Streptococcus pneumoniae most common except neonatesMore than 75 of total cases are caused by N meningitidis Strep pneumoniae and Hinfluenzae combined
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CAUSES OF SEPTIC SEPTIC SEPTIC SEPTIC MENINGITIS
AGE Most common Others
Birth to 3 months Streptococcus agalactiae Escherichia coli L monocytogenes
3 to 60 months Streptococcuspneumoniae
Neisseria meningitidis
H influenzae type b
gt 60 months Streptococcuspneumoniae
Neisseria meningitidis
L monocytogenes
Other Gram negative
organisms
Any age (cranial
surgery)
Staphylococcus aureus
Any age
(immunosuppressed)
L monocytogenes
Other Gram negatives
(including P aeroginosa)
Bacterial Virulence FactorsNeisseria meningitidis
Capsule IgA protease pili and endotoxinHaemophilus influenzae
Capsule IgA protease pili and endotoxin Streptococcus pneumoniae
Capsule and IgA protease only
Neisseria meningitidisGram negative coffee bean shaped intracellular (PMNs) exclusively human pathogenMany members of the genus are commensals of upper respiratory tractAbout 30 of the population may transiently carry N meningitidis Responsible for more than 75 cases of septic meningitis ( Reported by Dr Jungkind) Transmission is via droplet inhalationMore than 13 of the cases occur in the first five years of ageHigh morbidity and mortality ~50 survivors have neurologic or other sequelae
DiagnosisClinical signs- rash (Tumbler test) sepsis fever nuchal rigidityCSF tap- protein glucose and WBC count
Culture- fastidious organism requires 5-10 CO2
Blood or CSF sample- plate on chocolate agarNasopharyngeal swab- plate on to Modified Martin-Thayer agar
Contains antibiotics to inhibit normal biotaRapid techniques
Latex agglutinationPCR
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PreventionTetravalent vaccine composed of Groups A C Y and W135 (Group B is weaklyimmunogenic)
Protection is group specificProtection is limited to ~3 yearsVaccination does not protect from carriage of the organism
Vaccine is poorly immunogenic for infants under 2 years of age
Streptococcus agalactiae Beta hemolytic Taxos A resistant Group B streptococcusNormal female genital organism (~40 colonized))60 mortality for babies who develop meningitis during the first week of life
Premature birth is an important risk factorNeonates
Lethargy fever sepsis and respiratory distressChildren and adults
Puerperal fever at delivery and other skin and soft tissue infections
Streptococcus pneumoniaeGram positive lancet shaped alpha hemolytic Taxos P sensitive cocci (Optochin)Part of normal flora of 20 adults and gt75 healthy childrenMOST COMMON cause of bacterial meningitisHighest cause of infantile meningitisMortality rate for pneumococcal meningitis is ~25Neurological sequelae is ~50
In elderly it may follow pneumoniaMiddle ear infectionsSinusiPathogenesis (Braun et al2002 J Clin Invest 10919-27)
Pathogenesis
Hydrogen peroxide- due to absence of catalase large amounts accumulate and enhanceapoptosisPneumolysin
pore forming toxinPotent neurotoxin can trigger cellular apoptosis
Pathogenesis (Guikel et al2003 PNAS10014363-14367)In mouse models invasion can occur through nasopharynx (not hematogenous)Teichoic and lipoteichoic acids of cell wall mediate binding to the gangliosides expressedon the neuronsSubsequent travel is then via retrograde axonal transport along olfactory neurons
Haemophilus influenzae
Gram negative fastidious encapsulated pleomorphic organismsSpread via blood from respiratory tract to the brainInfection opportunity between 4 months to 3 yearsGreater risk of permanent neurologic damage than any other bacterial meningitisVaccines made with type B capsular polysaccharide
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Enterobacteriaceae
Escherichia coli K1Gram negative facultative anaerobesDuring pregnancy increased colonization of K1 strain with 8 mortality
Spreads from nasopharynx to the meningesEnterobacteriaceae Symptoms
lt1 month old- irritability lethargy vomiting lack of appetite and seizures4-18 months- nuchal rigidity tense fontanels and feverOlder children amp adults- headache vomiting confusion lethargy seizures and feve
Interactions during meningitis
Escherichia coli GI respiratory orgenitourinary tract
bloodstream
Slide kindly provided by Dr J Rayner
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Klebsiella pneumoniaeGram negative rodsHigh incidence in cockroach infested areasEarly onset- lt3 days- 2nd only to GBS
(leukopenia and neutropenia)Late onset- 8-28 days-2nd only to Staphylococcus
(leukocytosis and neutrophilia)Symptoms
Lethargy poor feeding little cry fever scleremaCulture from blood CSF urineC-reactive protein positive
Listeria monocytogenesGram positive non spore forming aerobic motile rodsEpidemiology
Food-borne (dairy and deli)Soil water decaying vegetation
Human intestines may be reservoir
2-12 humans carry the organismCan be transmitted to the baby during delivery (may cause spontaneous abortions)Pathogenesis
Grows in macrophagesReleases ldquoInternalinrdquo- as a cell attachment molecule trigger entryListeriolysin- protein that helps in movement within the cellHemolysin- pore-forming toxin Allows escape from phagosome to the phagosoleUses host cell actin to move to the new cells
DiagnosisIntracellular gram positive rods in macrophages and neutrophilsCSF culture- looks like β-Strep but catalase + and ldquotumblerdquo
Slide is kindly provided by Dr Rayner
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Spirochetes Infections of CNSTreponema pallidum
Early stages are infectious and no CNS involvementTakes about 10 year or longer for non treated cases
Neurosyphilis is the Tertiary stage of the disease and no longer infectiousDelayed hypersensitivity is part of the pathologic mechanism of tissue damageCommonly found in different tissues of the body as ldquoGummasrdquoInfection of CNS is via meningovascular routeSpirochetes Infections of CNSSymptoms
CNS degenerative changes resulting in mental changesMay have frank psychosisShuffling gait ldquotabes dorsalisrdquo
DiagnosisSpinal fluid may be helpfulElevated WBCs and protein
VDRL positive
Leptospira interogans Animals are reservoirsSpreads through animal urine contaminated water and food (survives weeks in water)No body of water in the US is free from itSensitive to Acid pH drying and soap~100 casesyearSewer workers miners veterinarians and meat packers are at risk Spirochetes Infections of CNSSymptoms
Incubation 7-13 days (range 5 days - 4 weeks)
Bacteremic phase- influenza like symptoms and fever (bacteria NOW enter the CNS)2 nd Phase - ~3+weeksHeadache with ldquoasepticrdquo meningitisSometimes hemodynamic collapse
DiagnosisBlood cultureCSF analysis and cultureRise in antibody between acute and convalescent stages
Borrelia burgdorferi~15 Neurologic abnormalities rarely fatal
Starts with a tick biteLarge spirochetes- 02x10-30 micromSpirochetes Infections of CNS
SymptomsClassic ldquobullrsquos eyerdquo rash fever joint pain meningeal irritation2nd Stage- dissemination system wide3rd Stage- mild neurologic or frank encephalitis
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DiagnosisLoose irregular spirals Silver or immunoflourescent stainDifficult to cultureCDC recommends antibody screen using ELISA
Fungal Infections of CNSDisseminate hematogenously from a remote site of infection (oropharynx or lung)Create multiple areas of infection within brain and other organsCan cause abscessesMeningoencephalitis occurs early by vascular invasion by fungusCan see secondary thrombosis cerebral infarction and hemorrhages
Common fungiCandida albicansCryptococcus neoformansHistoplasma capsulatumAspergillus fumigatus
DiagnosisAntibody studiesCXRCandida- forms granulomatus reaction Yeast forms seen with silver stainCryptococcus- fungi appear like encapsulated spheres Capsules can be seen bymucicarmine stain Histoplasma- CT scan Aspergillus- branching hyphae classical appearance
Please revisit your notes on Respiratory fungal infections by Dr Lennon
Encephalitis
EtiologyViral
Herpes viruses enteroviruses arboviruses rabies virus HIV HTLV-1Paramyxoviruses (mumps rubeola virus and arenaviruses)
Bacterial (RARE)Exceptions Legionella pneumoniae Borrelia burgdorferi Treponema pallidum
FungalCryptococcus neoformans
ParasiticPlasmodium falciparum Trypanosomes
MyelitisAcute inflammation of the spinal cord
Depending upon virus this can lead to flaccid paralysisSymptoms
HeadacheFeverIrritation followed by
Weakness of one or more extremitiesEtiology
Poliovirus was the leading cause before vaccinationWest Nile virus is the most significant after 2000
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Defined as inflammation of brain parenchymaEncephalitis is considered clinically a more severe syndrome than viral meningitisSymptoms
HeadacheFever
Altered consciousness-lethargy to confusion and comaBehavioral and speech disturbanceSeizures
Arboviruses Arthropod-borne viral infectionsDistributed worldwideTransmitted by mosquitoes and ticksSporadic and epidemic encephalitisSeizures are generally the complications in children
All arboviruses are enveloped viruses with icosahedral nucleocapsid and contain a transfecting RNA
Major families of arboviruses (Togaviridae and Flaviviridae )Togaviridae
Belongs to Baltimore Class IVbEarly and late proteins madeVirus buds at the plasma membrane
TogaviridaeVenezuelan Equine Encephalitis (VEE)Togaviridae (alphavirus)
Spread through Culex and Aedes mosquitoesSymptoms
Prodrome- fever chills weakness headache myalgia (due to viral replication )Rapid progression- nuchal rigidity confusion somnolence seizure in 50 of cases andcoma (due to spread through microvascular permeability of brain then cell-to-celloccurs via axon and dendrites )NO DEATHS in humans 80 mortality in horses
Eastern Equine Encephalitis (EEE)Common in North AmericaSpreads through Aedes and Culiseta spHumans are dead-end hosts but Aedes may spread from horse to human
Clinical symptoms similar to that of VEEHIGH MORTALITY in humans
Western Equine Encephalitis (WEE)Spreads through Culex and CulisetaCommon in rural areas of US in summer monthsFatality rate 3-4 death in 1-2 days Children have a 30 chance of CNS sequelae
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Pathophysiology of Equine EncephalitidesDefuse CNS involvementNeutrophils and macrophages infiltrate brain parenchyma causing focal necrosis and spottydemyelinationVascular inflammation with endothelial proliferation and small vessel thrombosis
EEELarge number of active virus entering in brain parenchymaEffects the perikaryon and dendrites of neurons with minimal glial cell infiltration
WEEDamage mediated by large number of immunologically active cells that enterbrainCell death by apoptosis primarily in the glial and inflammatory cells
FlaviviridaeBelongs to Baltimore class IVaPolyprotein is translated first which cleaves into many individual proteinsVirus buds inside cytoplasmic vesicles and the virus is released through
exocytosis
St Louis Encephalitis virus (SLE)Epidemiology
Transmitted by culex mosquitoesOvert infection depends upon
Efficiency of replication at extra neural sitesDegree of viremiaAge of the host
PathophysiologyVirus enters through BBB (astrocyte complex)
Or cross fenestrated endothelium (choroid plexus)Symptoms
Mortality 2-20 (higher in elderly)Malaise and fever only 20 develop sequelae (irritability memory loss movementdisorders motor deficits)Seizures and coma COMMONNo chronic illness
Japanese B Encephalitis virus (JBE)Epidemiology
Spread through Culex mosquitoesIncubation 4-14 days
Rural areas of AsiaSeptember 2010 India 319 deaths and Nepal 5 deaths
SymptomsViral prodrome- fever by 2nd weekEncephalitis syndrome with tremors NOT seizuresLow CSF IgGIgM ratio= higher death rate
West Nile Encephalitis virus (WNV)Epidemiology
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Wild birds are reservoir spreads through Aedes mosquitoes3-15 fatalVery RARE person to person transmission
SymptomsViral prodrome with maculopapular rash on trunk and extremitiesHeadache HIGH fever nuchal rigidity stupor tremor and seizures paralysis
BunyaviridaeAt least 200 different viruses included in this groupEnveloped viruses containing single-stranded negative polarity segmented (3) RNASpreads through mosquitoes ticks and flies
California Encephalitis virusLa Crosse virus
RhabdoviridaeLyssavirus RabiesStructure
Bullet shaped virusSingle-stranded negative polarity RNA
Helical nucleocapsid in an envelope5 proteins- NPMG and L
Surface glycoprotein attaches to cell receptors including Acetylcholine receptor atneuromuscular junctions
PathophysiologyViral entry into the cell is via endocytosisVirus has a preference for nerve and salivary gland cells (travels via axons to CNS)Spreads from brain to salivary glands kidneys and conjunctival cells (virus in tears )
EpidemiologyEstimated 35000-50000 cases worldwide
Highest in Asia ~90 casesEndozoonotic all warm blooded animals are susceptible
Urban- dogs and catsSylvatic- wildlife
SymptomsIncubation 20-90 days may extend to a yearNonspecific ndash general malaise fever headache (tingling pain and weakness at the bitsite)Progressive - neurologic symptoms including insomnia confusion slight or partialparalysis agitation hypersalivation dysphagia (hydrophobia)Paralytic ndashdisorientation stupor
Death within days after symptoms (~7 days)Diagnosis
Saliva- virus isolation RT-PCRSerum and CSF for rabies antibodies (FA and ELISA)Brain tissue- Negri bodies Babes nodules consisting of glial cells
TreatmentPrevention
Wash all wounds with soap and water
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1 dose of immune globulin and 4 doses of vaccine on days 137 amp14 days + 2boosters on days 0 and 3
New recommendations by CDC published on Mar 18 2010
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010(MMWR VOL59RR2 MAR 18 2010)
NOT PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent (eg povidine-iodinesolution) should be used to irrigate the wounds
Human rabies
immune globulin(HRIG)
Administer 20 IUkg body weight If anatomicallyfeasible the full dose should be infiltrated around and
into the wound(s) and any remaining volume shouldbe administered at an anatomical site (intramuscular
[IM]) distant from vaccine administration
Vaccine Human diploid cell vaccine (HDCV) or purified chickembryo cell vaccine (PCECV) 10 mL IM (deltoid but
never in the gluteal region) 1 each on days 0 3 7 and
14(For immunocompromised 5 shots)
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010
(MMWR VOL59RR2 MAR 18 2010)
PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent such as povidine-iodinesolution should be used to irrigate the wounds
HRIG HRIG should not be administered
Vaccine HDCV or PCECV 10 mL IM (deltoid but never in the
gluteal area) 1 each on days 0 and 3
For persons with immunosuppression rabies PEPshould be administered using all 5 doses of vaccine on
days 0 3 7 14 and 28
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Other virus infections of the CNSArenaviridae - Lymphocytic ChoriomeningitisTogaviridae- Rubella virusHerpesviridae - Human Herpes virus 1-8Retroviridae - HIV-1Other virus infections of the CNS
Papovaviridae - Polyoma virus (JC virus)-PML (Progressive Multifocal Leukoencephalopathy)Viral DNA in majority of healthy humansMultifocal signs including hemiparesis visual loss seizures dementia personalitychanges and gait problemsCharacteristic white matter lesions common in posterior occipital area
Paramyxoviridae - Mumps viruses and Measles- SSPE (Subacute Sclerosing Pan Encephalitis)Slow fatal condition after more than 10 years of measlesWorldwide more common in boys (31) than girlsBehavior changes in school age childrenFulminant course- 10 of cases death in 3 monthsChronic course- death in 4-10 years
Brain Abscess and EmpyemaLocalized bacterial infection of brain parenchyma and subdural or epidural spacesPressure from accumulation of exudates may permanently damage the brain tissueMay be fatal if not treated properlyAbscess
Fixed boundariesEmpyema
Lack of definable shape or sizeBrain Abscess
Symptoms
Usually are rapid and associated with their locationHeadacheChanges in mental status- drowsiness to comaGeneralized seizure
Fungal brain abscessDisseminated hematogenously from remote site ( lungs or oropharynx)Create multiple areas of infection within brainMeningoencephalitis occurs early by vascular invasionEtiology
Aspergillus Cryptococcus Candida
Transmissible Spongiform EncephalopathiesPrion is an abnormal isomer of normal host proteinNO NUCLEIC ACID presentReplicate without provoking antibody or inflammatory responseAre resistant to some inactivation methods used for bacteria and viruses (70 alcohol X-raysand UV light etc)Sensitive to autoclaving and bleachDisease confined to the CNS and may take decades to manifestCan be inherited (~15) of cases)
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PathogenesisNormal PrPc- glycoprotein with secondary structures dominated by Alpha helixPrion protein PrPSc- glycoprotein with secondary structures dominated by Beta-pleats When PrPSc molecules comes in contact with the normal PrPc molecule the normal PrPc changes into the abnormal PrPSc
Modified protein aggregates in neurons as myeloid plaques
Spongy appearance of cerebrum is due to the formation of vacuoles in the cortex andcerebellum
Spread of PrionsSporadic- no apparent causeInherited - through autosomal dominant traitIngestion - infected food cannibalism
Kuru-incubation ~20 yearsInvolves progressive trunchal shaking and unsteady gait Death within 3-24 months
Medical events- (Iatrogenic) through surgery organs etc
Creutzfeld Jekob Disease (CJD)Most common prion human diseasePeak incidence 55-65 years but can affect teenagersNo treatmentSymptoms
Insidious mental deteriorationEarly cerebellar and visual problemsSevere dementia in 6 monthsBrain and lower motor neuron involvementCases of CJD have been due to
Infected corneal transplantsReused improperly sterilized brain surgery equipment
Pituitary hormone injections derived from cadaversAccidental cuts during autopsies or surgeries
Bovine Variant of CJDBSE re-emerged in 1996 with progressive neurodegenerative disease resulting in patient deathNormally bovine but crossed to humans as Mad Cow DiseaseDiagnosis
Biopsy of BrainSpongiform encephalopathyAccumulation of abnormally folded protein
Sporadic diseaseCSF- no cells
CNS InfectionsThis was by no means a complete inventory of infectious agents involvedThere are many more however we discussed ONLY the very common and frequent infectionsThe original Mad Cow
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Moves into gut-associated lymphoid tissue eg Peyerrsquos patches (site of primaryreplication)Resulting viremia seeds peripheral tissue virus enters the neurons of the peripheralnervous system that innervates the peripheral tissues and the virus traffics to the CNSusing retrograde axonal transport
(Lancaster and Pfeiffer 2010)
Outcomes of infectionInapparent infections
95 asymptomatic virus in RESDiagnosis by virus isolation from feces and oropharynx and by specific serumantibodies
Abortive polio (minor illness)- flu like symptomsSimilar to any systemic viral infection
Polio encephalitis- RARENon-paralytic polio (aseptic meningitis)
Similar to other enteroviral meningitis
Paralytic polio (lt2 of cases)Viral spread is normally restricted due to
Limited replication of virus in peripheral neuronsInsufficient retrograde axonal transport in peripheral neuronsInnate resistance through IFN α β production
When these barriers are breeched the out come will be paralytic polioSpinal - flaccid paralysis due lysis of the anterior horn cellsBulbar - paralysis of cranial nerve IX and X medullarrespiratory centers
PreventionInactivated vaccine
Formalized Salk vaccine injected im
Local antibody is not producedMostly used in Western Hemisphere (where polio is considered eradicated)
Please see Table 56-2 in Murray et al 6 th Ed p 561 Live oral vaccine
Sabin vaccine is stable at room temperature with MgCl2Produces secretory antibodiesVirus can spread to contacts and enhance herd immunity and may causeparalytic polio (~1 in 4 million)
Please see Table 56-2 in Murray et al 6 th Ed p 561
Meningitis (Continued)
Septic (as opposed to viral Aseptic) Caused by bacteria onlyAssociated with high Mortality and SeverityEtiology is AGE dependent
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CAUSES OF SEPTIC SEPTIC SEPTIC SEPTIC MENINGITIS
AGE Most common Others
Birth to 3 months Streptococcus agalactiae Escherichia coli L monocytogenes
3 to 60 months Streptococcuspneumoniae
Neisseria meningitidis
H influenzae type b
gt 60 months Streptococcuspneumoniae
Neisseria meningitidis
L monocytogenes
Other Gram negative
organisms
Any age (cranial
surgery)
Staphylococcus aureus
Any age
(immunosuppressed)
L monocytogenes
Other Gram negatives
(including P aeroginosa)
Bacterial Infections of CNSOver 25 infectious agents involvedSevere life threatening infections requiring prompt diagnosis and treatmentSeptic meningitis (Bacterial meningitis)Bacterial invasion into CNS
Invasion from nearby siteMiddle ear or chronic sinusitis
Spread from a distant siteHematogenous invasion
Direct introductionRARE sometimes the source cannot be identified
Bacterial MeningitisNeonates- Strep agalactiae Coliforms and Listeria monocytogenesInfants- Streptococcus pneumoniae Neisseria meningitidis and H influenzaeChildren- Strep pneumoniae N meningitidis and Listeria monocytogenes Streptococcus pneumoniae most common except neonatesMore than 75 of total cases are caused by N meningitidis Strep pneumoniae and Hinfluenzae combined
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CAUSES OF SEPTIC SEPTIC SEPTIC SEPTIC MENINGITIS
AGE Most common Others
Birth to 3 months Streptococcus agalactiae Escherichia coli L monocytogenes
3 to 60 months Streptococcuspneumoniae
Neisseria meningitidis
H influenzae type b
gt 60 months Streptococcuspneumoniae
Neisseria meningitidis
L monocytogenes
Other Gram negative
organisms
Any age (cranial
surgery)
Staphylococcus aureus
Any age
(immunosuppressed)
L monocytogenes
Other Gram negatives
(including P aeroginosa)
Bacterial Virulence FactorsNeisseria meningitidis
Capsule IgA protease pili and endotoxinHaemophilus influenzae
Capsule IgA protease pili and endotoxin Streptococcus pneumoniae
Capsule and IgA protease only
Neisseria meningitidisGram negative coffee bean shaped intracellular (PMNs) exclusively human pathogenMany members of the genus are commensals of upper respiratory tractAbout 30 of the population may transiently carry N meningitidis Responsible for more than 75 cases of septic meningitis ( Reported by Dr Jungkind) Transmission is via droplet inhalationMore than 13 of the cases occur in the first five years of ageHigh morbidity and mortality ~50 survivors have neurologic or other sequelae
DiagnosisClinical signs- rash (Tumbler test) sepsis fever nuchal rigidityCSF tap- protein glucose and WBC count
Culture- fastidious organism requires 5-10 CO2
Blood or CSF sample- plate on chocolate agarNasopharyngeal swab- plate on to Modified Martin-Thayer agar
Contains antibiotics to inhibit normal biotaRapid techniques
Latex agglutinationPCR
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PreventionTetravalent vaccine composed of Groups A C Y and W135 (Group B is weaklyimmunogenic)
Protection is group specificProtection is limited to ~3 yearsVaccination does not protect from carriage of the organism
Vaccine is poorly immunogenic for infants under 2 years of age
Streptococcus agalactiae Beta hemolytic Taxos A resistant Group B streptococcusNormal female genital organism (~40 colonized))60 mortality for babies who develop meningitis during the first week of life
Premature birth is an important risk factorNeonates
Lethargy fever sepsis and respiratory distressChildren and adults
Puerperal fever at delivery and other skin and soft tissue infections
Streptococcus pneumoniaeGram positive lancet shaped alpha hemolytic Taxos P sensitive cocci (Optochin)Part of normal flora of 20 adults and gt75 healthy childrenMOST COMMON cause of bacterial meningitisHighest cause of infantile meningitisMortality rate for pneumococcal meningitis is ~25Neurological sequelae is ~50
In elderly it may follow pneumoniaMiddle ear infectionsSinusiPathogenesis (Braun et al2002 J Clin Invest 10919-27)
Pathogenesis
Hydrogen peroxide- due to absence of catalase large amounts accumulate and enhanceapoptosisPneumolysin
pore forming toxinPotent neurotoxin can trigger cellular apoptosis
Pathogenesis (Guikel et al2003 PNAS10014363-14367)In mouse models invasion can occur through nasopharynx (not hematogenous)Teichoic and lipoteichoic acids of cell wall mediate binding to the gangliosides expressedon the neuronsSubsequent travel is then via retrograde axonal transport along olfactory neurons
Haemophilus influenzae
Gram negative fastidious encapsulated pleomorphic organismsSpread via blood from respiratory tract to the brainInfection opportunity between 4 months to 3 yearsGreater risk of permanent neurologic damage than any other bacterial meningitisVaccines made with type B capsular polysaccharide
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Enterobacteriaceae
Escherichia coli K1Gram negative facultative anaerobesDuring pregnancy increased colonization of K1 strain with 8 mortality
Spreads from nasopharynx to the meningesEnterobacteriaceae Symptoms
lt1 month old- irritability lethargy vomiting lack of appetite and seizures4-18 months- nuchal rigidity tense fontanels and feverOlder children amp adults- headache vomiting confusion lethargy seizures and feve
Interactions during meningitis
Escherichia coli GI respiratory orgenitourinary tract
bloodstream
Slide kindly provided by Dr J Rayner
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Klebsiella pneumoniaeGram negative rodsHigh incidence in cockroach infested areasEarly onset- lt3 days- 2nd only to GBS
(leukopenia and neutropenia)Late onset- 8-28 days-2nd only to Staphylococcus
(leukocytosis and neutrophilia)Symptoms
Lethargy poor feeding little cry fever scleremaCulture from blood CSF urineC-reactive protein positive
Listeria monocytogenesGram positive non spore forming aerobic motile rodsEpidemiology
Food-borne (dairy and deli)Soil water decaying vegetation
Human intestines may be reservoir
2-12 humans carry the organismCan be transmitted to the baby during delivery (may cause spontaneous abortions)Pathogenesis
Grows in macrophagesReleases ldquoInternalinrdquo- as a cell attachment molecule trigger entryListeriolysin- protein that helps in movement within the cellHemolysin- pore-forming toxin Allows escape from phagosome to the phagosoleUses host cell actin to move to the new cells
DiagnosisIntracellular gram positive rods in macrophages and neutrophilsCSF culture- looks like β-Strep but catalase + and ldquotumblerdquo
Slide is kindly provided by Dr Rayner
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Spirochetes Infections of CNSTreponema pallidum
Early stages are infectious and no CNS involvementTakes about 10 year or longer for non treated cases
Neurosyphilis is the Tertiary stage of the disease and no longer infectiousDelayed hypersensitivity is part of the pathologic mechanism of tissue damageCommonly found in different tissues of the body as ldquoGummasrdquoInfection of CNS is via meningovascular routeSpirochetes Infections of CNSSymptoms
CNS degenerative changes resulting in mental changesMay have frank psychosisShuffling gait ldquotabes dorsalisrdquo
DiagnosisSpinal fluid may be helpfulElevated WBCs and protein
VDRL positive
Leptospira interogans Animals are reservoirsSpreads through animal urine contaminated water and food (survives weeks in water)No body of water in the US is free from itSensitive to Acid pH drying and soap~100 casesyearSewer workers miners veterinarians and meat packers are at risk Spirochetes Infections of CNSSymptoms
Incubation 7-13 days (range 5 days - 4 weeks)
Bacteremic phase- influenza like symptoms and fever (bacteria NOW enter the CNS)2 nd Phase - ~3+weeksHeadache with ldquoasepticrdquo meningitisSometimes hemodynamic collapse
DiagnosisBlood cultureCSF analysis and cultureRise in antibody between acute and convalescent stages
Borrelia burgdorferi~15 Neurologic abnormalities rarely fatal
Starts with a tick biteLarge spirochetes- 02x10-30 micromSpirochetes Infections of CNS
SymptomsClassic ldquobullrsquos eyerdquo rash fever joint pain meningeal irritation2nd Stage- dissemination system wide3rd Stage- mild neurologic or frank encephalitis
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DiagnosisLoose irregular spirals Silver or immunoflourescent stainDifficult to cultureCDC recommends antibody screen using ELISA
Fungal Infections of CNSDisseminate hematogenously from a remote site of infection (oropharynx or lung)Create multiple areas of infection within brain and other organsCan cause abscessesMeningoencephalitis occurs early by vascular invasion by fungusCan see secondary thrombosis cerebral infarction and hemorrhages
Common fungiCandida albicansCryptococcus neoformansHistoplasma capsulatumAspergillus fumigatus
DiagnosisAntibody studiesCXRCandida- forms granulomatus reaction Yeast forms seen with silver stainCryptococcus- fungi appear like encapsulated spheres Capsules can be seen bymucicarmine stain Histoplasma- CT scan Aspergillus- branching hyphae classical appearance
Please revisit your notes on Respiratory fungal infections by Dr Lennon
Encephalitis
EtiologyViral
Herpes viruses enteroviruses arboviruses rabies virus HIV HTLV-1Paramyxoviruses (mumps rubeola virus and arenaviruses)
Bacterial (RARE)Exceptions Legionella pneumoniae Borrelia burgdorferi Treponema pallidum
FungalCryptococcus neoformans
ParasiticPlasmodium falciparum Trypanosomes
MyelitisAcute inflammation of the spinal cord
Depending upon virus this can lead to flaccid paralysisSymptoms
HeadacheFeverIrritation followed by
Weakness of one or more extremitiesEtiology
Poliovirus was the leading cause before vaccinationWest Nile virus is the most significant after 2000
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Defined as inflammation of brain parenchymaEncephalitis is considered clinically a more severe syndrome than viral meningitisSymptoms
HeadacheFever
Altered consciousness-lethargy to confusion and comaBehavioral and speech disturbanceSeizures
Arboviruses Arthropod-borne viral infectionsDistributed worldwideTransmitted by mosquitoes and ticksSporadic and epidemic encephalitisSeizures are generally the complications in children
All arboviruses are enveloped viruses with icosahedral nucleocapsid and contain a transfecting RNA
Major families of arboviruses (Togaviridae and Flaviviridae )Togaviridae
Belongs to Baltimore Class IVbEarly and late proteins madeVirus buds at the plasma membrane
TogaviridaeVenezuelan Equine Encephalitis (VEE)Togaviridae (alphavirus)
Spread through Culex and Aedes mosquitoesSymptoms
Prodrome- fever chills weakness headache myalgia (due to viral replication )Rapid progression- nuchal rigidity confusion somnolence seizure in 50 of cases andcoma (due to spread through microvascular permeability of brain then cell-to-celloccurs via axon and dendrites )NO DEATHS in humans 80 mortality in horses
Eastern Equine Encephalitis (EEE)Common in North AmericaSpreads through Aedes and Culiseta spHumans are dead-end hosts but Aedes may spread from horse to human
Clinical symptoms similar to that of VEEHIGH MORTALITY in humans
Western Equine Encephalitis (WEE)Spreads through Culex and CulisetaCommon in rural areas of US in summer monthsFatality rate 3-4 death in 1-2 days Children have a 30 chance of CNS sequelae
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Pathophysiology of Equine EncephalitidesDefuse CNS involvementNeutrophils and macrophages infiltrate brain parenchyma causing focal necrosis and spottydemyelinationVascular inflammation with endothelial proliferation and small vessel thrombosis
EEELarge number of active virus entering in brain parenchymaEffects the perikaryon and dendrites of neurons with minimal glial cell infiltration
WEEDamage mediated by large number of immunologically active cells that enterbrainCell death by apoptosis primarily in the glial and inflammatory cells
FlaviviridaeBelongs to Baltimore class IVaPolyprotein is translated first which cleaves into many individual proteinsVirus buds inside cytoplasmic vesicles and the virus is released through
exocytosis
St Louis Encephalitis virus (SLE)Epidemiology
Transmitted by culex mosquitoesOvert infection depends upon
Efficiency of replication at extra neural sitesDegree of viremiaAge of the host
PathophysiologyVirus enters through BBB (astrocyte complex)
Or cross fenestrated endothelium (choroid plexus)Symptoms
Mortality 2-20 (higher in elderly)Malaise and fever only 20 develop sequelae (irritability memory loss movementdisorders motor deficits)Seizures and coma COMMONNo chronic illness
Japanese B Encephalitis virus (JBE)Epidemiology
Spread through Culex mosquitoesIncubation 4-14 days
Rural areas of AsiaSeptember 2010 India 319 deaths and Nepal 5 deaths
SymptomsViral prodrome- fever by 2nd weekEncephalitis syndrome with tremors NOT seizuresLow CSF IgGIgM ratio= higher death rate
West Nile Encephalitis virus (WNV)Epidemiology
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Wild birds are reservoir spreads through Aedes mosquitoes3-15 fatalVery RARE person to person transmission
SymptomsViral prodrome with maculopapular rash on trunk and extremitiesHeadache HIGH fever nuchal rigidity stupor tremor and seizures paralysis
BunyaviridaeAt least 200 different viruses included in this groupEnveloped viruses containing single-stranded negative polarity segmented (3) RNASpreads through mosquitoes ticks and flies
California Encephalitis virusLa Crosse virus
RhabdoviridaeLyssavirus RabiesStructure
Bullet shaped virusSingle-stranded negative polarity RNA
Helical nucleocapsid in an envelope5 proteins- NPMG and L
Surface glycoprotein attaches to cell receptors including Acetylcholine receptor atneuromuscular junctions
PathophysiologyViral entry into the cell is via endocytosisVirus has a preference for nerve and salivary gland cells (travels via axons to CNS)Spreads from brain to salivary glands kidneys and conjunctival cells (virus in tears )
EpidemiologyEstimated 35000-50000 cases worldwide
Highest in Asia ~90 casesEndozoonotic all warm blooded animals are susceptible
Urban- dogs and catsSylvatic- wildlife
SymptomsIncubation 20-90 days may extend to a yearNonspecific ndash general malaise fever headache (tingling pain and weakness at the bitsite)Progressive - neurologic symptoms including insomnia confusion slight or partialparalysis agitation hypersalivation dysphagia (hydrophobia)Paralytic ndashdisorientation stupor
Death within days after symptoms (~7 days)Diagnosis
Saliva- virus isolation RT-PCRSerum and CSF for rabies antibodies (FA and ELISA)Brain tissue- Negri bodies Babes nodules consisting of glial cells
TreatmentPrevention
Wash all wounds with soap and water
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1 dose of immune globulin and 4 doses of vaccine on days 137 amp14 days + 2boosters on days 0 and 3
New recommendations by CDC published on Mar 18 2010
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010(MMWR VOL59RR2 MAR 18 2010)
NOT PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent (eg povidine-iodinesolution) should be used to irrigate the wounds
Human rabies
immune globulin(HRIG)
Administer 20 IUkg body weight If anatomicallyfeasible the full dose should be infiltrated around and
into the wound(s) and any remaining volume shouldbe administered at an anatomical site (intramuscular
[IM]) distant from vaccine administration
Vaccine Human diploid cell vaccine (HDCV) or purified chickembryo cell vaccine (PCECV) 10 mL IM (deltoid but
never in the gluteal region) 1 each on days 0 3 7 and
14(For immunocompromised 5 shots)
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010
(MMWR VOL59RR2 MAR 18 2010)
PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent such as povidine-iodinesolution should be used to irrigate the wounds
HRIG HRIG should not be administered
Vaccine HDCV or PCECV 10 mL IM (deltoid but never in the
gluteal area) 1 each on days 0 and 3
For persons with immunosuppression rabies PEPshould be administered using all 5 doses of vaccine on
days 0 3 7 14 and 28
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Other virus infections of the CNSArenaviridae - Lymphocytic ChoriomeningitisTogaviridae- Rubella virusHerpesviridae - Human Herpes virus 1-8Retroviridae - HIV-1Other virus infections of the CNS
Papovaviridae - Polyoma virus (JC virus)-PML (Progressive Multifocal Leukoencephalopathy)Viral DNA in majority of healthy humansMultifocal signs including hemiparesis visual loss seizures dementia personalitychanges and gait problemsCharacteristic white matter lesions common in posterior occipital area
Paramyxoviridae - Mumps viruses and Measles- SSPE (Subacute Sclerosing Pan Encephalitis)Slow fatal condition after more than 10 years of measlesWorldwide more common in boys (31) than girlsBehavior changes in school age childrenFulminant course- 10 of cases death in 3 monthsChronic course- death in 4-10 years
Brain Abscess and EmpyemaLocalized bacterial infection of brain parenchyma and subdural or epidural spacesPressure from accumulation of exudates may permanently damage the brain tissueMay be fatal if not treated properlyAbscess
Fixed boundariesEmpyema
Lack of definable shape or sizeBrain Abscess
Symptoms
Usually are rapid and associated with their locationHeadacheChanges in mental status- drowsiness to comaGeneralized seizure
Fungal brain abscessDisseminated hematogenously from remote site ( lungs or oropharynx)Create multiple areas of infection within brainMeningoencephalitis occurs early by vascular invasionEtiology
Aspergillus Cryptococcus Candida
Transmissible Spongiform EncephalopathiesPrion is an abnormal isomer of normal host proteinNO NUCLEIC ACID presentReplicate without provoking antibody or inflammatory responseAre resistant to some inactivation methods used for bacteria and viruses (70 alcohol X-raysand UV light etc)Sensitive to autoclaving and bleachDisease confined to the CNS and may take decades to manifestCan be inherited (~15) of cases)
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PathogenesisNormal PrPc- glycoprotein with secondary structures dominated by Alpha helixPrion protein PrPSc- glycoprotein with secondary structures dominated by Beta-pleats When PrPSc molecules comes in contact with the normal PrPc molecule the normal PrPc changes into the abnormal PrPSc
Modified protein aggregates in neurons as myeloid plaques
Spongy appearance of cerebrum is due to the formation of vacuoles in the cortex andcerebellum
Spread of PrionsSporadic- no apparent causeInherited - through autosomal dominant traitIngestion - infected food cannibalism
Kuru-incubation ~20 yearsInvolves progressive trunchal shaking and unsteady gait Death within 3-24 months
Medical events- (Iatrogenic) through surgery organs etc
Creutzfeld Jekob Disease (CJD)Most common prion human diseasePeak incidence 55-65 years but can affect teenagersNo treatmentSymptoms
Insidious mental deteriorationEarly cerebellar and visual problemsSevere dementia in 6 monthsBrain and lower motor neuron involvementCases of CJD have been due to
Infected corneal transplantsReused improperly sterilized brain surgery equipment
Pituitary hormone injections derived from cadaversAccidental cuts during autopsies or surgeries
Bovine Variant of CJDBSE re-emerged in 1996 with progressive neurodegenerative disease resulting in patient deathNormally bovine but crossed to humans as Mad Cow DiseaseDiagnosis
Biopsy of BrainSpongiform encephalopathyAccumulation of abnormally folded protein
Sporadic diseaseCSF- no cells
CNS InfectionsThis was by no means a complete inventory of infectious agents involvedThere are many more however we discussed ONLY the very common and frequent infectionsThe original Mad Cow
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CAUSES OF SEPTIC SEPTIC SEPTIC SEPTIC MENINGITIS
AGE Most common Others
Birth to 3 months Streptococcus agalactiae Escherichia coli L monocytogenes
3 to 60 months Streptococcuspneumoniae
Neisseria meningitidis
H influenzae type b
gt 60 months Streptococcuspneumoniae
Neisseria meningitidis
L monocytogenes
Other Gram negative
organisms
Any age (cranial
surgery)
Staphylococcus aureus
Any age
(immunosuppressed)
L monocytogenes
Other Gram negatives
(including P aeroginosa)
Bacterial Infections of CNSOver 25 infectious agents involvedSevere life threatening infections requiring prompt diagnosis and treatmentSeptic meningitis (Bacterial meningitis)Bacterial invasion into CNS
Invasion from nearby siteMiddle ear or chronic sinusitis
Spread from a distant siteHematogenous invasion
Direct introductionRARE sometimes the source cannot be identified
Bacterial MeningitisNeonates- Strep agalactiae Coliforms and Listeria monocytogenesInfants- Streptococcus pneumoniae Neisseria meningitidis and H influenzaeChildren- Strep pneumoniae N meningitidis and Listeria monocytogenes Streptococcus pneumoniae most common except neonatesMore than 75 of total cases are caused by N meningitidis Strep pneumoniae and Hinfluenzae combined
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CAUSES OF SEPTIC SEPTIC SEPTIC SEPTIC MENINGITIS
AGE Most common Others
Birth to 3 months Streptococcus agalactiae Escherichia coli L monocytogenes
3 to 60 months Streptococcuspneumoniae
Neisseria meningitidis
H influenzae type b
gt 60 months Streptococcuspneumoniae
Neisseria meningitidis
L monocytogenes
Other Gram negative
organisms
Any age (cranial
surgery)
Staphylococcus aureus
Any age
(immunosuppressed)
L monocytogenes
Other Gram negatives
(including P aeroginosa)
Bacterial Virulence FactorsNeisseria meningitidis
Capsule IgA protease pili and endotoxinHaemophilus influenzae
Capsule IgA protease pili and endotoxin Streptococcus pneumoniae
Capsule and IgA protease only
Neisseria meningitidisGram negative coffee bean shaped intracellular (PMNs) exclusively human pathogenMany members of the genus are commensals of upper respiratory tractAbout 30 of the population may transiently carry N meningitidis Responsible for more than 75 cases of septic meningitis ( Reported by Dr Jungkind) Transmission is via droplet inhalationMore than 13 of the cases occur in the first five years of ageHigh morbidity and mortality ~50 survivors have neurologic or other sequelae
DiagnosisClinical signs- rash (Tumbler test) sepsis fever nuchal rigidityCSF tap- protein glucose and WBC count
Culture- fastidious organism requires 5-10 CO2
Blood or CSF sample- plate on chocolate agarNasopharyngeal swab- plate on to Modified Martin-Thayer agar
Contains antibiotics to inhibit normal biotaRapid techniques
Latex agglutinationPCR
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
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983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983090
PreventionTetravalent vaccine composed of Groups A C Y and W135 (Group B is weaklyimmunogenic)
Protection is group specificProtection is limited to ~3 yearsVaccination does not protect from carriage of the organism
Vaccine is poorly immunogenic for infants under 2 years of age
Streptococcus agalactiae Beta hemolytic Taxos A resistant Group B streptococcusNormal female genital organism (~40 colonized))60 mortality for babies who develop meningitis during the first week of life
Premature birth is an important risk factorNeonates
Lethargy fever sepsis and respiratory distressChildren and adults
Puerperal fever at delivery and other skin and soft tissue infections
Streptococcus pneumoniaeGram positive lancet shaped alpha hemolytic Taxos P sensitive cocci (Optochin)Part of normal flora of 20 adults and gt75 healthy childrenMOST COMMON cause of bacterial meningitisHighest cause of infantile meningitisMortality rate for pneumococcal meningitis is ~25Neurological sequelae is ~50
In elderly it may follow pneumoniaMiddle ear infectionsSinusiPathogenesis (Braun et al2002 J Clin Invest 10919-27)
Pathogenesis
Hydrogen peroxide- due to absence of catalase large amounts accumulate and enhanceapoptosisPneumolysin
pore forming toxinPotent neurotoxin can trigger cellular apoptosis
Pathogenesis (Guikel et al2003 PNAS10014363-14367)In mouse models invasion can occur through nasopharynx (not hematogenous)Teichoic and lipoteichoic acids of cell wall mediate binding to the gangliosides expressedon the neuronsSubsequent travel is then via retrograde axonal transport along olfactory neurons
Haemophilus influenzae
Gram negative fastidious encapsulated pleomorphic organismsSpread via blood from respiratory tract to the brainInfection opportunity between 4 months to 3 yearsGreater risk of permanent neurologic damage than any other bacterial meningitisVaccines made with type B capsular polysaccharide
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983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983091
Enterobacteriaceae
Escherichia coli K1Gram negative facultative anaerobesDuring pregnancy increased colonization of K1 strain with 8 mortality
Spreads from nasopharynx to the meningesEnterobacteriaceae Symptoms
lt1 month old- irritability lethargy vomiting lack of appetite and seizures4-18 months- nuchal rigidity tense fontanels and feverOlder children amp adults- headache vomiting confusion lethargy seizures and feve
Interactions during meningitis
Escherichia coli GI respiratory orgenitourinary tract
bloodstream
Slide kindly provided by Dr J Rayner
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983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983092
Klebsiella pneumoniaeGram negative rodsHigh incidence in cockroach infested areasEarly onset- lt3 days- 2nd only to GBS
(leukopenia and neutropenia)Late onset- 8-28 days-2nd only to Staphylococcus
(leukocytosis and neutrophilia)Symptoms
Lethargy poor feeding little cry fever scleremaCulture from blood CSF urineC-reactive protein positive
Listeria monocytogenesGram positive non spore forming aerobic motile rodsEpidemiology
Food-borne (dairy and deli)Soil water decaying vegetation
Human intestines may be reservoir
2-12 humans carry the organismCan be transmitted to the baby during delivery (may cause spontaneous abortions)Pathogenesis
Grows in macrophagesReleases ldquoInternalinrdquo- as a cell attachment molecule trigger entryListeriolysin- protein that helps in movement within the cellHemolysin- pore-forming toxin Allows escape from phagosome to the phagosoleUses host cell actin to move to the new cells
DiagnosisIntracellular gram positive rods in macrophages and neutrophilsCSF culture- looks like β-Strep but catalase + and ldquotumblerdquo
Slide is kindly provided by Dr Rayner
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 1522
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983093
Spirochetes Infections of CNSTreponema pallidum
Early stages are infectious and no CNS involvementTakes about 10 year or longer for non treated cases
Neurosyphilis is the Tertiary stage of the disease and no longer infectiousDelayed hypersensitivity is part of the pathologic mechanism of tissue damageCommonly found in different tissues of the body as ldquoGummasrdquoInfection of CNS is via meningovascular routeSpirochetes Infections of CNSSymptoms
CNS degenerative changes resulting in mental changesMay have frank psychosisShuffling gait ldquotabes dorsalisrdquo
DiagnosisSpinal fluid may be helpfulElevated WBCs and protein
VDRL positive
Leptospira interogans Animals are reservoirsSpreads through animal urine contaminated water and food (survives weeks in water)No body of water in the US is free from itSensitive to Acid pH drying and soap~100 casesyearSewer workers miners veterinarians and meat packers are at risk Spirochetes Infections of CNSSymptoms
Incubation 7-13 days (range 5 days - 4 weeks)
Bacteremic phase- influenza like symptoms and fever (bacteria NOW enter the CNS)2 nd Phase - ~3+weeksHeadache with ldquoasepticrdquo meningitisSometimes hemodynamic collapse
DiagnosisBlood cultureCSF analysis and cultureRise in antibody between acute and convalescent stages
Borrelia burgdorferi~15 Neurologic abnormalities rarely fatal
Starts with a tick biteLarge spirochetes- 02x10-30 micromSpirochetes Infections of CNS
SymptomsClassic ldquobullrsquos eyerdquo rash fever joint pain meningeal irritation2nd Stage- dissemination system wide3rd Stage- mild neurologic or frank encephalitis
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
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983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983094
DiagnosisLoose irregular spirals Silver or immunoflourescent stainDifficult to cultureCDC recommends antibody screen using ELISA
Fungal Infections of CNSDisseminate hematogenously from a remote site of infection (oropharynx or lung)Create multiple areas of infection within brain and other organsCan cause abscessesMeningoencephalitis occurs early by vascular invasion by fungusCan see secondary thrombosis cerebral infarction and hemorrhages
Common fungiCandida albicansCryptococcus neoformansHistoplasma capsulatumAspergillus fumigatus
DiagnosisAntibody studiesCXRCandida- forms granulomatus reaction Yeast forms seen with silver stainCryptococcus- fungi appear like encapsulated spheres Capsules can be seen bymucicarmine stain Histoplasma- CT scan Aspergillus- branching hyphae classical appearance
Please revisit your notes on Respiratory fungal infections by Dr Lennon
Encephalitis
EtiologyViral
Herpes viruses enteroviruses arboviruses rabies virus HIV HTLV-1Paramyxoviruses (mumps rubeola virus and arenaviruses)
Bacterial (RARE)Exceptions Legionella pneumoniae Borrelia burgdorferi Treponema pallidum
FungalCryptococcus neoformans
ParasiticPlasmodium falciparum Trypanosomes
MyelitisAcute inflammation of the spinal cord
Depending upon virus this can lead to flaccid paralysisSymptoms
HeadacheFeverIrritation followed by
Weakness of one or more extremitiesEtiology
Poliovirus was the leading cause before vaccinationWest Nile virus is the most significant after 2000
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
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Defined as inflammation of brain parenchymaEncephalitis is considered clinically a more severe syndrome than viral meningitisSymptoms
HeadacheFever
Altered consciousness-lethargy to confusion and comaBehavioral and speech disturbanceSeizures
Arboviruses Arthropod-borne viral infectionsDistributed worldwideTransmitted by mosquitoes and ticksSporadic and epidemic encephalitisSeizures are generally the complications in children
All arboviruses are enveloped viruses with icosahedral nucleocapsid and contain a transfecting RNA
Major families of arboviruses (Togaviridae and Flaviviridae )Togaviridae
Belongs to Baltimore Class IVbEarly and late proteins madeVirus buds at the plasma membrane
TogaviridaeVenezuelan Equine Encephalitis (VEE)Togaviridae (alphavirus)
Spread through Culex and Aedes mosquitoesSymptoms
Prodrome- fever chills weakness headache myalgia (due to viral replication )Rapid progression- nuchal rigidity confusion somnolence seizure in 50 of cases andcoma (due to spread through microvascular permeability of brain then cell-to-celloccurs via axon and dendrites )NO DEATHS in humans 80 mortality in horses
Eastern Equine Encephalitis (EEE)Common in North AmericaSpreads through Aedes and Culiseta spHumans are dead-end hosts but Aedes may spread from horse to human
Clinical symptoms similar to that of VEEHIGH MORTALITY in humans
Western Equine Encephalitis (WEE)Spreads through Culex and CulisetaCommon in rural areas of US in summer monthsFatality rate 3-4 death in 1-2 days Children have a 30 chance of CNS sequelae
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
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983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983096
Pathophysiology of Equine EncephalitidesDefuse CNS involvementNeutrophils and macrophages infiltrate brain parenchyma causing focal necrosis and spottydemyelinationVascular inflammation with endothelial proliferation and small vessel thrombosis
EEELarge number of active virus entering in brain parenchymaEffects the perikaryon and dendrites of neurons with minimal glial cell infiltration
WEEDamage mediated by large number of immunologically active cells that enterbrainCell death by apoptosis primarily in the glial and inflammatory cells
FlaviviridaeBelongs to Baltimore class IVaPolyprotein is translated first which cleaves into many individual proteinsVirus buds inside cytoplasmic vesicles and the virus is released through
exocytosis
St Louis Encephalitis virus (SLE)Epidemiology
Transmitted by culex mosquitoesOvert infection depends upon
Efficiency of replication at extra neural sitesDegree of viremiaAge of the host
PathophysiologyVirus enters through BBB (astrocyte complex)
Or cross fenestrated endothelium (choroid plexus)Symptoms
Mortality 2-20 (higher in elderly)Malaise and fever only 20 develop sequelae (irritability memory loss movementdisorders motor deficits)Seizures and coma COMMONNo chronic illness
Japanese B Encephalitis virus (JBE)Epidemiology
Spread through Culex mosquitoesIncubation 4-14 days
Rural areas of AsiaSeptember 2010 India 319 deaths and Nepal 5 deaths
SymptomsViral prodrome- fever by 2nd weekEncephalitis syndrome with tremors NOT seizuresLow CSF IgGIgM ratio= higher death rate
West Nile Encephalitis virus (WNV)Epidemiology
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983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983097
Wild birds are reservoir spreads through Aedes mosquitoes3-15 fatalVery RARE person to person transmission
SymptomsViral prodrome with maculopapular rash on trunk and extremitiesHeadache HIGH fever nuchal rigidity stupor tremor and seizures paralysis
BunyaviridaeAt least 200 different viruses included in this groupEnveloped viruses containing single-stranded negative polarity segmented (3) RNASpreads through mosquitoes ticks and flies
California Encephalitis virusLa Crosse virus
RhabdoviridaeLyssavirus RabiesStructure
Bullet shaped virusSingle-stranded negative polarity RNA
Helical nucleocapsid in an envelope5 proteins- NPMG and L
Surface glycoprotein attaches to cell receptors including Acetylcholine receptor atneuromuscular junctions
PathophysiologyViral entry into the cell is via endocytosisVirus has a preference for nerve and salivary gland cells (travels via axons to CNS)Spreads from brain to salivary glands kidneys and conjunctival cells (virus in tears )
EpidemiologyEstimated 35000-50000 cases worldwide
Highest in Asia ~90 casesEndozoonotic all warm blooded animals are susceptible
Urban- dogs and catsSylvatic- wildlife
SymptomsIncubation 20-90 days may extend to a yearNonspecific ndash general malaise fever headache (tingling pain and weakness at the bitsite)Progressive - neurologic symptoms including insomnia confusion slight or partialparalysis agitation hypersalivation dysphagia (hydrophobia)Paralytic ndashdisorientation stupor
Death within days after symptoms (~7 days)Diagnosis
Saliva- virus isolation RT-PCRSerum and CSF for rabies antibodies (FA and ELISA)Brain tissue- Negri bodies Babes nodules consisting of glial cells
TreatmentPrevention
Wash all wounds with soap and water
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
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983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983088
1 dose of immune globulin and 4 doses of vaccine on days 137 amp14 days + 2boosters on days 0 and 3
New recommendations by CDC published on Mar 18 2010
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010(MMWR VOL59RR2 MAR 18 2010)
NOT PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent (eg povidine-iodinesolution) should be used to irrigate the wounds
Human rabies
immune globulin(HRIG)
Administer 20 IUkg body weight If anatomicallyfeasible the full dose should be infiltrated around and
into the wound(s) and any remaining volume shouldbe administered at an anatomical site (intramuscular
[IM]) distant from vaccine administration
Vaccine Human diploid cell vaccine (HDCV) or purified chickembryo cell vaccine (PCECV) 10 mL IM (deltoid but
never in the gluteal region) 1 each on days 0 3 7 and
14(For immunocompromised 5 shots)
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010
(MMWR VOL59RR2 MAR 18 2010)
PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent such as povidine-iodinesolution should be used to irrigate the wounds
HRIG HRIG should not be administered
Vaccine HDCV or PCECV 10 mL IM (deltoid but never in the
gluteal area) 1 each on days 0 and 3
For persons with immunosuppression rabies PEPshould be administered using all 5 doses of vaccine on
days 0 3 7 14 and 28
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
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Other virus infections of the CNSArenaviridae - Lymphocytic ChoriomeningitisTogaviridae- Rubella virusHerpesviridae - Human Herpes virus 1-8Retroviridae - HIV-1Other virus infections of the CNS
Papovaviridae - Polyoma virus (JC virus)-PML (Progressive Multifocal Leukoencephalopathy)Viral DNA in majority of healthy humansMultifocal signs including hemiparesis visual loss seizures dementia personalitychanges and gait problemsCharacteristic white matter lesions common in posterior occipital area
Paramyxoviridae - Mumps viruses and Measles- SSPE (Subacute Sclerosing Pan Encephalitis)Slow fatal condition after more than 10 years of measlesWorldwide more common in boys (31) than girlsBehavior changes in school age childrenFulminant course- 10 of cases death in 3 monthsChronic course- death in 4-10 years
Brain Abscess and EmpyemaLocalized bacterial infection of brain parenchyma and subdural or epidural spacesPressure from accumulation of exudates may permanently damage the brain tissueMay be fatal if not treated properlyAbscess
Fixed boundariesEmpyema
Lack of definable shape or sizeBrain Abscess
Symptoms
Usually are rapid and associated with their locationHeadacheChanges in mental status- drowsiness to comaGeneralized seizure
Fungal brain abscessDisseminated hematogenously from remote site ( lungs or oropharynx)Create multiple areas of infection within brainMeningoencephalitis occurs early by vascular invasionEtiology
Aspergillus Cryptococcus Candida
Transmissible Spongiform EncephalopathiesPrion is an abnormal isomer of normal host proteinNO NUCLEIC ACID presentReplicate without provoking antibody or inflammatory responseAre resistant to some inactivation methods used for bacteria and viruses (70 alcohol X-raysand UV light etc)Sensitive to autoclaving and bleachDisease confined to the CNS and may take decades to manifestCan be inherited (~15) of cases)
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PathogenesisNormal PrPc- glycoprotein with secondary structures dominated by Alpha helixPrion protein PrPSc- glycoprotein with secondary structures dominated by Beta-pleats When PrPSc molecules comes in contact with the normal PrPc molecule the normal PrPc changes into the abnormal PrPSc
Modified protein aggregates in neurons as myeloid plaques
Spongy appearance of cerebrum is due to the formation of vacuoles in the cortex andcerebellum
Spread of PrionsSporadic- no apparent causeInherited - through autosomal dominant traitIngestion - infected food cannibalism
Kuru-incubation ~20 yearsInvolves progressive trunchal shaking and unsteady gait Death within 3-24 months
Medical events- (Iatrogenic) through surgery organs etc
Creutzfeld Jekob Disease (CJD)Most common prion human diseasePeak incidence 55-65 years but can affect teenagersNo treatmentSymptoms
Insidious mental deteriorationEarly cerebellar and visual problemsSevere dementia in 6 monthsBrain and lower motor neuron involvementCases of CJD have been due to
Infected corneal transplantsReused improperly sterilized brain surgery equipment
Pituitary hormone injections derived from cadaversAccidental cuts during autopsies or surgeries
Bovine Variant of CJDBSE re-emerged in 1996 with progressive neurodegenerative disease resulting in patient deathNormally bovine but crossed to humans as Mad Cow DiseaseDiagnosis
Biopsy of BrainSpongiform encephalopathyAccumulation of abnormally folded protein
Sporadic diseaseCSF- no cells
CNS InfectionsThis was by no means a complete inventory of infectious agents involvedThere are many more however we discussed ONLY the very common and frequent infectionsThe original Mad Cow
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CAUSES OF SEPTIC SEPTIC SEPTIC SEPTIC MENINGITIS
AGE Most common Others
Birth to 3 months Streptococcus agalactiae Escherichia coli L monocytogenes
3 to 60 months Streptococcuspneumoniae
Neisseria meningitidis
H influenzae type b
gt 60 months Streptococcuspneumoniae
Neisseria meningitidis
L monocytogenes
Other Gram negative
organisms
Any age (cranial
surgery)
Staphylococcus aureus
Any age
(immunosuppressed)
L monocytogenes
Other Gram negatives
(including P aeroginosa)
Bacterial Virulence FactorsNeisseria meningitidis
Capsule IgA protease pili and endotoxinHaemophilus influenzae
Capsule IgA protease pili and endotoxin Streptococcus pneumoniae
Capsule and IgA protease only
Neisseria meningitidisGram negative coffee bean shaped intracellular (PMNs) exclusively human pathogenMany members of the genus are commensals of upper respiratory tractAbout 30 of the population may transiently carry N meningitidis Responsible for more than 75 cases of septic meningitis ( Reported by Dr Jungkind) Transmission is via droplet inhalationMore than 13 of the cases occur in the first five years of ageHigh morbidity and mortality ~50 survivors have neurologic or other sequelae
DiagnosisClinical signs- rash (Tumbler test) sepsis fever nuchal rigidityCSF tap- protein glucose and WBC count
Culture- fastidious organism requires 5-10 CO2
Blood or CSF sample- plate on chocolate agarNasopharyngeal swab- plate on to Modified Martin-Thayer agar
Contains antibiotics to inhibit normal biotaRapid techniques
Latex agglutinationPCR
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PreventionTetravalent vaccine composed of Groups A C Y and W135 (Group B is weaklyimmunogenic)
Protection is group specificProtection is limited to ~3 yearsVaccination does not protect from carriage of the organism
Vaccine is poorly immunogenic for infants under 2 years of age
Streptococcus agalactiae Beta hemolytic Taxos A resistant Group B streptococcusNormal female genital organism (~40 colonized))60 mortality for babies who develop meningitis during the first week of life
Premature birth is an important risk factorNeonates
Lethargy fever sepsis and respiratory distressChildren and adults
Puerperal fever at delivery and other skin and soft tissue infections
Streptococcus pneumoniaeGram positive lancet shaped alpha hemolytic Taxos P sensitive cocci (Optochin)Part of normal flora of 20 adults and gt75 healthy childrenMOST COMMON cause of bacterial meningitisHighest cause of infantile meningitisMortality rate for pneumococcal meningitis is ~25Neurological sequelae is ~50
In elderly it may follow pneumoniaMiddle ear infectionsSinusiPathogenesis (Braun et al2002 J Clin Invest 10919-27)
Pathogenesis
Hydrogen peroxide- due to absence of catalase large amounts accumulate and enhanceapoptosisPneumolysin
pore forming toxinPotent neurotoxin can trigger cellular apoptosis
Pathogenesis (Guikel et al2003 PNAS10014363-14367)In mouse models invasion can occur through nasopharynx (not hematogenous)Teichoic and lipoteichoic acids of cell wall mediate binding to the gangliosides expressedon the neuronsSubsequent travel is then via retrograde axonal transport along olfactory neurons
Haemophilus influenzae
Gram negative fastidious encapsulated pleomorphic organismsSpread via blood from respiratory tract to the brainInfection opportunity between 4 months to 3 yearsGreater risk of permanent neurologic damage than any other bacterial meningitisVaccines made with type B capsular polysaccharide
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
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983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983091
Enterobacteriaceae
Escherichia coli K1Gram negative facultative anaerobesDuring pregnancy increased colonization of K1 strain with 8 mortality
Spreads from nasopharynx to the meningesEnterobacteriaceae Symptoms
lt1 month old- irritability lethargy vomiting lack of appetite and seizures4-18 months- nuchal rigidity tense fontanels and feverOlder children amp adults- headache vomiting confusion lethargy seizures and feve
Interactions during meningitis
Escherichia coli GI respiratory orgenitourinary tract
bloodstream
Slide kindly provided by Dr J Rayner
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
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983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983092
Klebsiella pneumoniaeGram negative rodsHigh incidence in cockroach infested areasEarly onset- lt3 days- 2nd only to GBS
(leukopenia and neutropenia)Late onset- 8-28 days-2nd only to Staphylococcus
(leukocytosis and neutrophilia)Symptoms
Lethargy poor feeding little cry fever scleremaCulture from blood CSF urineC-reactive protein positive
Listeria monocytogenesGram positive non spore forming aerobic motile rodsEpidemiology
Food-borne (dairy and deli)Soil water decaying vegetation
Human intestines may be reservoir
2-12 humans carry the organismCan be transmitted to the baby during delivery (may cause spontaneous abortions)Pathogenesis
Grows in macrophagesReleases ldquoInternalinrdquo- as a cell attachment molecule trigger entryListeriolysin- protein that helps in movement within the cellHemolysin- pore-forming toxin Allows escape from phagosome to the phagosoleUses host cell actin to move to the new cells
DiagnosisIntracellular gram positive rods in macrophages and neutrophilsCSF culture- looks like β-Strep but catalase + and ldquotumblerdquo
Slide is kindly provided by Dr Rayner
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
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983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983093
Spirochetes Infections of CNSTreponema pallidum
Early stages are infectious and no CNS involvementTakes about 10 year or longer for non treated cases
Neurosyphilis is the Tertiary stage of the disease and no longer infectiousDelayed hypersensitivity is part of the pathologic mechanism of tissue damageCommonly found in different tissues of the body as ldquoGummasrdquoInfection of CNS is via meningovascular routeSpirochetes Infections of CNSSymptoms
CNS degenerative changes resulting in mental changesMay have frank psychosisShuffling gait ldquotabes dorsalisrdquo
DiagnosisSpinal fluid may be helpfulElevated WBCs and protein
VDRL positive
Leptospira interogans Animals are reservoirsSpreads through animal urine contaminated water and food (survives weeks in water)No body of water in the US is free from itSensitive to Acid pH drying and soap~100 casesyearSewer workers miners veterinarians and meat packers are at risk Spirochetes Infections of CNSSymptoms
Incubation 7-13 days (range 5 days - 4 weeks)
Bacteremic phase- influenza like symptoms and fever (bacteria NOW enter the CNS)2 nd Phase - ~3+weeksHeadache with ldquoasepticrdquo meningitisSometimes hemodynamic collapse
DiagnosisBlood cultureCSF analysis and cultureRise in antibody between acute and convalescent stages
Borrelia burgdorferi~15 Neurologic abnormalities rarely fatal
Starts with a tick biteLarge spirochetes- 02x10-30 micromSpirochetes Infections of CNS
SymptomsClassic ldquobullrsquos eyerdquo rash fever joint pain meningeal irritation2nd Stage- dissemination system wide3rd Stage- mild neurologic or frank encephalitis
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
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983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983094
DiagnosisLoose irregular spirals Silver or immunoflourescent stainDifficult to cultureCDC recommends antibody screen using ELISA
Fungal Infections of CNSDisseminate hematogenously from a remote site of infection (oropharynx or lung)Create multiple areas of infection within brain and other organsCan cause abscessesMeningoencephalitis occurs early by vascular invasion by fungusCan see secondary thrombosis cerebral infarction and hemorrhages
Common fungiCandida albicansCryptococcus neoformansHistoplasma capsulatumAspergillus fumigatus
DiagnosisAntibody studiesCXRCandida- forms granulomatus reaction Yeast forms seen with silver stainCryptococcus- fungi appear like encapsulated spheres Capsules can be seen bymucicarmine stain Histoplasma- CT scan Aspergillus- branching hyphae classical appearance
Please revisit your notes on Respiratory fungal infections by Dr Lennon
Encephalitis
EtiologyViral
Herpes viruses enteroviruses arboviruses rabies virus HIV HTLV-1Paramyxoviruses (mumps rubeola virus and arenaviruses)
Bacterial (RARE)Exceptions Legionella pneumoniae Borrelia burgdorferi Treponema pallidum
FungalCryptococcus neoformans
ParasiticPlasmodium falciparum Trypanosomes
MyelitisAcute inflammation of the spinal cord
Depending upon virus this can lead to flaccid paralysisSymptoms
HeadacheFeverIrritation followed by
Weakness of one or more extremitiesEtiology
Poliovirus was the leading cause before vaccinationWest Nile virus is the most significant after 2000
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983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983095
Defined as inflammation of brain parenchymaEncephalitis is considered clinically a more severe syndrome than viral meningitisSymptoms
HeadacheFever
Altered consciousness-lethargy to confusion and comaBehavioral and speech disturbanceSeizures
Arboviruses Arthropod-borne viral infectionsDistributed worldwideTransmitted by mosquitoes and ticksSporadic and epidemic encephalitisSeizures are generally the complications in children
All arboviruses are enveloped viruses with icosahedral nucleocapsid and contain a transfecting RNA
Major families of arboviruses (Togaviridae and Flaviviridae )Togaviridae
Belongs to Baltimore Class IVbEarly and late proteins madeVirus buds at the plasma membrane
TogaviridaeVenezuelan Equine Encephalitis (VEE)Togaviridae (alphavirus)
Spread through Culex and Aedes mosquitoesSymptoms
Prodrome- fever chills weakness headache myalgia (due to viral replication )Rapid progression- nuchal rigidity confusion somnolence seizure in 50 of cases andcoma (due to spread through microvascular permeability of brain then cell-to-celloccurs via axon and dendrites )NO DEATHS in humans 80 mortality in horses
Eastern Equine Encephalitis (EEE)Common in North AmericaSpreads through Aedes and Culiseta spHumans are dead-end hosts but Aedes may spread from horse to human
Clinical symptoms similar to that of VEEHIGH MORTALITY in humans
Western Equine Encephalitis (WEE)Spreads through Culex and CulisetaCommon in rural areas of US in summer monthsFatality rate 3-4 death in 1-2 days Children have a 30 chance of CNS sequelae
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
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983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983096
Pathophysiology of Equine EncephalitidesDefuse CNS involvementNeutrophils and macrophages infiltrate brain parenchyma causing focal necrosis and spottydemyelinationVascular inflammation with endothelial proliferation and small vessel thrombosis
EEELarge number of active virus entering in brain parenchymaEffects the perikaryon and dendrites of neurons with minimal glial cell infiltration
WEEDamage mediated by large number of immunologically active cells that enterbrainCell death by apoptosis primarily in the glial and inflammatory cells
FlaviviridaeBelongs to Baltimore class IVaPolyprotein is translated first which cleaves into many individual proteinsVirus buds inside cytoplasmic vesicles and the virus is released through
exocytosis
St Louis Encephalitis virus (SLE)Epidemiology
Transmitted by culex mosquitoesOvert infection depends upon
Efficiency of replication at extra neural sitesDegree of viremiaAge of the host
PathophysiologyVirus enters through BBB (astrocyte complex)
Or cross fenestrated endothelium (choroid plexus)Symptoms
Mortality 2-20 (higher in elderly)Malaise and fever only 20 develop sequelae (irritability memory loss movementdisorders motor deficits)Seizures and coma COMMONNo chronic illness
Japanese B Encephalitis virus (JBE)Epidemiology
Spread through Culex mosquitoesIncubation 4-14 days
Rural areas of AsiaSeptember 2010 India 319 deaths and Nepal 5 deaths
SymptomsViral prodrome- fever by 2nd weekEncephalitis syndrome with tremors NOT seizuresLow CSF IgGIgM ratio= higher death rate
West Nile Encephalitis virus (WNV)Epidemiology
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
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983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983097
Wild birds are reservoir spreads through Aedes mosquitoes3-15 fatalVery RARE person to person transmission
SymptomsViral prodrome with maculopapular rash on trunk and extremitiesHeadache HIGH fever nuchal rigidity stupor tremor and seizures paralysis
BunyaviridaeAt least 200 different viruses included in this groupEnveloped viruses containing single-stranded negative polarity segmented (3) RNASpreads through mosquitoes ticks and flies
California Encephalitis virusLa Crosse virus
RhabdoviridaeLyssavirus RabiesStructure
Bullet shaped virusSingle-stranded negative polarity RNA
Helical nucleocapsid in an envelope5 proteins- NPMG and L
Surface glycoprotein attaches to cell receptors including Acetylcholine receptor atneuromuscular junctions
PathophysiologyViral entry into the cell is via endocytosisVirus has a preference for nerve and salivary gland cells (travels via axons to CNS)Spreads from brain to salivary glands kidneys and conjunctival cells (virus in tears )
EpidemiologyEstimated 35000-50000 cases worldwide
Highest in Asia ~90 casesEndozoonotic all warm blooded animals are susceptible
Urban- dogs and catsSylvatic- wildlife
SymptomsIncubation 20-90 days may extend to a yearNonspecific ndash general malaise fever headache (tingling pain and weakness at the bitsite)Progressive - neurologic symptoms including insomnia confusion slight or partialparalysis agitation hypersalivation dysphagia (hydrophobia)Paralytic ndashdisorientation stupor
Death within days after symptoms (~7 days)Diagnosis
Saliva- virus isolation RT-PCRSerum and CSF for rabies antibodies (FA and ELISA)Brain tissue- Negri bodies Babes nodules consisting of glial cells
TreatmentPrevention
Wash all wounds with soap and water
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
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983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983088
1 dose of immune globulin and 4 doses of vaccine on days 137 amp14 days + 2boosters on days 0 and 3
New recommendations by CDC published on Mar 18 2010
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010(MMWR VOL59RR2 MAR 18 2010)
NOT PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent (eg povidine-iodinesolution) should be used to irrigate the wounds
Human rabies
immune globulin(HRIG)
Administer 20 IUkg body weight If anatomicallyfeasible the full dose should be infiltrated around and
into the wound(s) and any remaining volume shouldbe administered at an anatomical site (intramuscular
[IM]) distant from vaccine administration
Vaccine Human diploid cell vaccine (HDCV) or purified chickembryo cell vaccine (PCECV) 10 mL IM (deltoid but
never in the gluteal region) 1 each on days 0 3 7 and
14(For immunocompromised 5 shots)
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010
(MMWR VOL59RR2 MAR 18 2010)
PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent such as povidine-iodinesolution should be used to irrigate the wounds
HRIG HRIG should not be administered
Vaccine HDCV or PCECV 10 mL IM (deltoid but never in the
gluteal area) 1 each on days 0 and 3
For persons with immunosuppression rabies PEPshould be administered using all 5 doses of vaccine on
days 0 3 7 14 and 28
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Other virus infections of the CNSArenaviridae - Lymphocytic ChoriomeningitisTogaviridae- Rubella virusHerpesviridae - Human Herpes virus 1-8Retroviridae - HIV-1Other virus infections of the CNS
Papovaviridae - Polyoma virus (JC virus)-PML (Progressive Multifocal Leukoencephalopathy)Viral DNA in majority of healthy humansMultifocal signs including hemiparesis visual loss seizures dementia personalitychanges and gait problemsCharacteristic white matter lesions common in posterior occipital area
Paramyxoviridae - Mumps viruses and Measles- SSPE (Subacute Sclerosing Pan Encephalitis)Slow fatal condition after more than 10 years of measlesWorldwide more common in boys (31) than girlsBehavior changes in school age childrenFulminant course- 10 of cases death in 3 monthsChronic course- death in 4-10 years
Brain Abscess and EmpyemaLocalized bacterial infection of brain parenchyma and subdural or epidural spacesPressure from accumulation of exudates may permanently damage the brain tissueMay be fatal if not treated properlyAbscess
Fixed boundariesEmpyema
Lack of definable shape or sizeBrain Abscess
Symptoms
Usually are rapid and associated with their locationHeadacheChanges in mental status- drowsiness to comaGeneralized seizure
Fungal brain abscessDisseminated hematogenously from remote site ( lungs or oropharynx)Create multiple areas of infection within brainMeningoencephalitis occurs early by vascular invasionEtiology
Aspergillus Cryptococcus Candida
Transmissible Spongiform EncephalopathiesPrion is an abnormal isomer of normal host proteinNO NUCLEIC ACID presentReplicate without provoking antibody or inflammatory responseAre resistant to some inactivation methods used for bacteria and viruses (70 alcohol X-raysand UV light etc)Sensitive to autoclaving and bleachDisease confined to the CNS and may take decades to manifestCan be inherited (~15) of cases)
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983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983090
PathogenesisNormal PrPc- glycoprotein with secondary structures dominated by Alpha helixPrion protein PrPSc- glycoprotein with secondary structures dominated by Beta-pleats When PrPSc molecules comes in contact with the normal PrPc molecule the normal PrPc changes into the abnormal PrPSc
Modified protein aggregates in neurons as myeloid plaques
Spongy appearance of cerebrum is due to the formation of vacuoles in the cortex andcerebellum
Spread of PrionsSporadic- no apparent causeInherited - through autosomal dominant traitIngestion - infected food cannibalism
Kuru-incubation ~20 yearsInvolves progressive trunchal shaking and unsteady gait Death within 3-24 months
Medical events- (Iatrogenic) through surgery organs etc
Creutzfeld Jekob Disease (CJD)Most common prion human diseasePeak incidence 55-65 years but can affect teenagersNo treatmentSymptoms
Insidious mental deteriorationEarly cerebellar and visual problemsSevere dementia in 6 monthsBrain and lower motor neuron involvementCases of CJD have been due to
Infected corneal transplantsReused improperly sterilized brain surgery equipment
Pituitary hormone injections derived from cadaversAccidental cuts during autopsies or surgeries
Bovine Variant of CJDBSE re-emerged in 1996 with progressive neurodegenerative disease resulting in patient deathNormally bovine but crossed to humans as Mad Cow DiseaseDiagnosis
Biopsy of BrainSpongiform encephalopathyAccumulation of abnormally folded protein
Sporadic diseaseCSF- no cells
CNS InfectionsThis was by no means a complete inventory of infectious agents involvedThere are many more however we discussed ONLY the very common and frequent infectionsThe original Mad Cow
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PreventionTetravalent vaccine composed of Groups A C Y and W135 (Group B is weaklyimmunogenic)
Protection is group specificProtection is limited to ~3 yearsVaccination does not protect from carriage of the organism
Vaccine is poorly immunogenic for infants under 2 years of age
Streptococcus agalactiae Beta hemolytic Taxos A resistant Group B streptococcusNormal female genital organism (~40 colonized))60 mortality for babies who develop meningitis during the first week of life
Premature birth is an important risk factorNeonates
Lethargy fever sepsis and respiratory distressChildren and adults
Puerperal fever at delivery and other skin and soft tissue infections
Streptococcus pneumoniaeGram positive lancet shaped alpha hemolytic Taxos P sensitive cocci (Optochin)Part of normal flora of 20 adults and gt75 healthy childrenMOST COMMON cause of bacterial meningitisHighest cause of infantile meningitisMortality rate for pneumococcal meningitis is ~25Neurological sequelae is ~50
In elderly it may follow pneumoniaMiddle ear infectionsSinusiPathogenesis (Braun et al2002 J Clin Invest 10919-27)
Pathogenesis
Hydrogen peroxide- due to absence of catalase large amounts accumulate and enhanceapoptosisPneumolysin
pore forming toxinPotent neurotoxin can trigger cellular apoptosis
Pathogenesis (Guikel et al2003 PNAS10014363-14367)In mouse models invasion can occur through nasopharynx (not hematogenous)Teichoic and lipoteichoic acids of cell wall mediate binding to the gangliosides expressedon the neuronsSubsequent travel is then via retrograde axonal transport along olfactory neurons
Haemophilus influenzae
Gram negative fastidious encapsulated pleomorphic organismsSpread via blood from respiratory tract to the brainInfection opportunity between 4 months to 3 yearsGreater risk of permanent neurologic damage than any other bacterial meningitisVaccines made with type B capsular polysaccharide
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Enterobacteriaceae
Escherichia coli K1Gram negative facultative anaerobesDuring pregnancy increased colonization of K1 strain with 8 mortality
Spreads from nasopharynx to the meningesEnterobacteriaceae Symptoms
lt1 month old- irritability lethargy vomiting lack of appetite and seizures4-18 months- nuchal rigidity tense fontanels and feverOlder children amp adults- headache vomiting confusion lethargy seizures and feve
Interactions during meningitis
Escherichia coli GI respiratory orgenitourinary tract
bloodstream
Slide kindly provided by Dr J Rayner
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Klebsiella pneumoniaeGram negative rodsHigh incidence in cockroach infested areasEarly onset- lt3 days- 2nd only to GBS
(leukopenia and neutropenia)Late onset- 8-28 days-2nd only to Staphylococcus
(leukocytosis and neutrophilia)Symptoms
Lethargy poor feeding little cry fever scleremaCulture from blood CSF urineC-reactive protein positive
Listeria monocytogenesGram positive non spore forming aerobic motile rodsEpidemiology
Food-borne (dairy and deli)Soil water decaying vegetation
Human intestines may be reservoir
2-12 humans carry the organismCan be transmitted to the baby during delivery (may cause spontaneous abortions)Pathogenesis
Grows in macrophagesReleases ldquoInternalinrdquo- as a cell attachment molecule trigger entryListeriolysin- protein that helps in movement within the cellHemolysin- pore-forming toxin Allows escape from phagosome to the phagosoleUses host cell actin to move to the new cells
DiagnosisIntracellular gram positive rods in macrophages and neutrophilsCSF culture- looks like β-Strep but catalase + and ldquotumblerdquo
Slide is kindly provided by Dr Rayner
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Spirochetes Infections of CNSTreponema pallidum
Early stages are infectious and no CNS involvementTakes about 10 year or longer for non treated cases
Neurosyphilis is the Tertiary stage of the disease and no longer infectiousDelayed hypersensitivity is part of the pathologic mechanism of tissue damageCommonly found in different tissues of the body as ldquoGummasrdquoInfection of CNS is via meningovascular routeSpirochetes Infections of CNSSymptoms
CNS degenerative changes resulting in mental changesMay have frank psychosisShuffling gait ldquotabes dorsalisrdquo
DiagnosisSpinal fluid may be helpfulElevated WBCs and protein
VDRL positive
Leptospira interogans Animals are reservoirsSpreads through animal urine contaminated water and food (survives weeks in water)No body of water in the US is free from itSensitive to Acid pH drying and soap~100 casesyearSewer workers miners veterinarians and meat packers are at risk Spirochetes Infections of CNSSymptoms
Incubation 7-13 days (range 5 days - 4 weeks)
Bacteremic phase- influenza like symptoms and fever (bacteria NOW enter the CNS)2 nd Phase - ~3+weeksHeadache with ldquoasepticrdquo meningitisSometimes hemodynamic collapse
DiagnosisBlood cultureCSF analysis and cultureRise in antibody between acute and convalescent stages
Borrelia burgdorferi~15 Neurologic abnormalities rarely fatal
Starts with a tick biteLarge spirochetes- 02x10-30 micromSpirochetes Infections of CNS
SymptomsClassic ldquobullrsquos eyerdquo rash fever joint pain meningeal irritation2nd Stage- dissemination system wide3rd Stage- mild neurologic or frank encephalitis
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DiagnosisLoose irregular spirals Silver or immunoflourescent stainDifficult to cultureCDC recommends antibody screen using ELISA
Fungal Infections of CNSDisseminate hematogenously from a remote site of infection (oropharynx or lung)Create multiple areas of infection within brain and other organsCan cause abscessesMeningoencephalitis occurs early by vascular invasion by fungusCan see secondary thrombosis cerebral infarction and hemorrhages
Common fungiCandida albicansCryptococcus neoformansHistoplasma capsulatumAspergillus fumigatus
DiagnosisAntibody studiesCXRCandida- forms granulomatus reaction Yeast forms seen with silver stainCryptococcus- fungi appear like encapsulated spheres Capsules can be seen bymucicarmine stain Histoplasma- CT scan Aspergillus- branching hyphae classical appearance
Please revisit your notes on Respiratory fungal infections by Dr Lennon
Encephalitis
EtiologyViral
Herpes viruses enteroviruses arboviruses rabies virus HIV HTLV-1Paramyxoviruses (mumps rubeola virus and arenaviruses)
Bacterial (RARE)Exceptions Legionella pneumoniae Borrelia burgdorferi Treponema pallidum
FungalCryptococcus neoformans
ParasiticPlasmodium falciparum Trypanosomes
MyelitisAcute inflammation of the spinal cord
Depending upon virus this can lead to flaccid paralysisSymptoms
HeadacheFeverIrritation followed by
Weakness of one or more extremitiesEtiology
Poliovirus was the leading cause before vaccinationWest Nile virus is the most significant after 2000
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
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983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983095
Defined as inflammation of brain parenchymaEncephalitis is considered clinically a more severe syndrome than viral meningitisSymptoms
HeadacheFever
Altered consciousness-lethargy to confusion and comaBehavioral and speech disturbanceSeizures
Arboviruses Arthropod-borne viral infectionsDistributed worldwideTransmitted by mosquitoes and ticksSporadic and epidemic encephalitisSeizures are generally the complications in children
All arboviruses are enveloped viruses with icosahedral nucleocapsid and contain a transfecting RNA
Major families of arboviruses (Togaviridae and Flaviviridae )Togaviridae
Belongs to Baltimore Class IVbEarly and late proteins madeVirus buds at the plasma membrane
TogaviridaeVenezuelan Equine Encephalitis (VEE)Togaviridae (alphavirus)
Spread through Culex and Aedes mosquitoesSymptoms
Prodrome- fever chills weakness headache myalgia (due to viral replication )Rapid progression- nuchal rigidity confusion somnolence seizure in 50 of cases andcoma (due to spread through microvascular permeability of brain then cell-to-celloccurs via axon and dendrites )NO DEATHS in humans 80 mortality in horses
Eastern Equine Encephalitis (EEE)Common in North AmericaSpreads through Aedes and Culiseta spHumans are dead-end hosts but Aedes may spread from horse to human
Clinical symptoms similar to that of VEEHIGH MORTALITY in humans
Western Equine Encephalitis (WEE)Spreads through Culex and CulisetaCommon in rural areas of US in summer monthsFatality rate 3-4 death in 1-2 days Children have a 30 chance of CNS sequelae
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
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983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983096
Pathophysiology of Equine EncephalitidesDefuse CNS involvementNeutrophils and macrophages infiltrate brain parenchyma causing focal necrosis and spottydemyelinationVascular inflammation with endothelial proliferation and small vessel thrombosis
EEELarge number of active virus entering in brain parenchymaEffects the perikaryon and dendrites of neurons with minimal glial cell infiltration
WEEDamage mediated by large number of immunologically active cells that enterbrainCell death by apoptosis primarily in the glial and inflammatory cells
FlaviviridaeBelongs to Baltimore class IVaPolyprotein is translated first which cleaves into many individual proteinsVirus buds inside cytoplasmic vesicles and the virus is released through
exocytosis
St Louis Encephalitis virus (SLE)Epidemiology
Transmitted by culex mosquitoesOvert infection depends upon
Efficiency of replication at extra neural sitesDegree of viremiaAge of the host
PathophysiologyVirus enters through BBB (astrocyte complex)
Or cross fenestrated endothelium (choroid plexus)Symptoms
Mortality 2-20 (higher in elderly)Malaise and fever only 20 develop sequelae (irritability memory loss movementdisorders motor deficits)Seizures and coma COMMONNo chronic illness
Japanese B Encephalitis virus (JBE)Epidemiology
Spread through Culex mosquitoesIncubation 4-14 days
Rural areas of AsiaSeptember 2010 India 319 deaths and Nepal 5 deaths
SymptomsViral prodrome- fever by 2nd weekEncephalitis syndrome with tremors NOT seizuresLow CSF IgGIgM ratio= higher death rate
West Nile Encephalitis virus (WNV)Epidemiology
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
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983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983097
Wild birds are reservoir spreads through Aedes mosquitoes3-15 fatalVery RARE person to person transmission
SymptomsViral prodrome with maculopapular rash on trunk and extremitiesHeadache HIGH fever nuchal rigidity stupor tremor and seizures paralysis
BunyaviridaeAt least 200 different viruses included in this groupEnveloped viruses containing single-stranded negative polarity segmented (3) RNASpreads through mosquitoes ticks and flies
California Encephalitis virusLa Crosse virus
RhabdoviridaeLyssavirus RabiesStructure
Bullet shaped virusSingle-stranded negative polarity RNA
Helical nucleocapsid in an envelope5 proteins- NPMG and L
Surface glycoprotein attaches to cell receptors including Acetylcholine receptor atneuromuscular junctions
PathophysiologyViral entry into the cell is via endocytosisVirus has a preference for nerve and salivary gland cells (travels via axons to CNS)Spreads from brain to salivary glands kidneys and conjunctival cells (virus in tears )
EpidemiologyEstimated 35000-50000 cases worldwide
Highest in Asia ~90 casesEndozoonotic all warm blooded animals are susceptible
Urban- dogs and catsSylvatic- wildlife
SymptomsIncubation 20-90 days may extend to a yearNonspecific ndash general malaise fever headache (tingling pain and weakness at the bitsite)Progressive - neurologic symptoms including insomnia confusion slight or partialparalysis agitation hypersalivation dysphagia (hydrophobia)Paralytic ndashdisorientation stupor
Death within days after symptoms (~7 days)Diagnosis
Saliva- virus isolation RT-PCRSerum and CSF for rabies antibodies (FA and ELISA)Brain tissue- Negri bodies Babes nodules consisting of glial cells
TreatmentPrevention
Wash all wounds with soap and water
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2022
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983088
1 dose of immune globulin and 4 doses of vaccine on days 137 amp14 days + 2boosters on days 0 and 3
New recommendations by CDC published on Mar 18 2010
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010(MMWR VOL59RR2 MAR 18 2010)
NOT PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent (eg povidine-iodinesolution) should be used to irrigate the wounds
Human rabies
immune globulin(HRIG)
Administer 20 IUkg body weight If anatomicallyfeasible the full dose should be infiltrated around and
into the wound(s) and any remaining volume shouldbe administered at an anatomical site (intramuscular
[IM]) distant from vaccine administration
Vaccine Human diploid cell vaccine (HDCV) or purified chickembryo cell vaccine (PCECV) 10 mL IM (deltoid but
never in the gluteal region) 1 each on days 0 3 7 and
14(For immunocompromised 5 shots)
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010
(MMWR VOL59RR2 MAR 18 2010)
PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent such as povidine-iodinesolution should be used to irrigate the wounds
HRIG HRIG should not be administered
Vaccine HDCV or PCECV 10 mL IM (deltoid but never in the
gluteal area) 1 each on days 0 and 3
For persons with immunosuppression rabies PEPshould be administered using all 5 doses of vaccine on
days 0 3 7 14 and 28
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2122
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983089
Other virus infections of the CNSArenaviridae - Lymphocytic ChoriomeningitisTogaviridae- Rubella virusHerpesviridae - Human Herpes virus 1-8Retroviridae - HIV-1Other virus infections of the CNS
Papovaviridae - Polyoma virus (JC virus)-PML (Progressive Multifocal Leukoencephalopathy)Viral DNA in majority of healthy humansMultifocal signs including hemiparesis visual loss seizures dementia personalitychanges and gait problemsCharacteristic white matter lesions common in posterior occipital area
Paramyxoviridae - Mumps viruses and Measles- SSPE (Subacute Sclerosing Pan Encephalitis)Slow fatal condition after more than 10 years of measlesWorldwide more common in boys (31) than girlsBehavior changes in school age childrenFulminant course- 10 of cases death in 3 monthsChronic course- death in 4-10 years
Brain Abscess and EmpyemaLocalized bacterial infection of brain parenchyma and subdural or epidural spacesPressure from accumulation of exudates may permanently damage the brain tissueMay be fatal if not treated properlyAbscess
Fixed boundariesEmpyema
Lack of definable shape or sizeBrain Abscess
Symptoms
Usually are rapid and associated with their locationHeadacheChanges in mental status- drowsiness to comaGeneralized seizure
Fungal brain abscessDisseminated hematogenously from remote site ( lungs or oropharynx)Create multiple areas of infection within brainMeningoencephalitis occurs early by vascular invasionEtiology
Aspergillus Cryptococcus Candida
Transmissible Spongiform EncephalopathiesPrion is an abnormal isomer of normal host proteinNO NUCLEIC ACID presentReplicate without provoking antibody or inflammatory responseAre resistant to some inactivation methods used for bacteria and viruses (70 alcohol X-raysand UV light etc)Sensitive to autoclaving and bleachDisease confined to the CNS and may take decades to manifestCan be inherited (~15) of cases)
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2222
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983090
PathogenesisNormal PrPc- glycoprotein with secondary structures dominated by Alpha helixPrion protein PrPSc- glycoprotein with secondary structures dominated by Beta-pleats When PrPSc molecules comes in contact with the normal PrPc molecule the normal PrPc changes into the abnormal PrPSc
Modified protein aggregates in neurons as myeloid plaques
Spongy appearance of cerebrum is due to the formation of vacuoles in the cortex andcerebellum
Spread of PrionsSporadic- no apparent causeInherited - through autosomal dominant traitIngestion - infected food cannibalism
Kuru-incubation ~20 yearsInvolves progressive trunchal shaking and unsteady gait Death within 3-24 months
Medical events- (Iatrogenic) through surgery organs etc
Creutzfeld Jekob Disease (CJD)Most common prion human diseasePeak incidence 55-65 years but can affect teenagersNo treatmentSymptoms
Insidious mental deteriorationEarly cerebellar and visual problemsSevere dementia in 6 monthsBrain and lower motor neuron involvementCases of CJD have been due to
Infected corneal transplantsReused improperly sterilized brain surgery equipment
Pituitary hormone injections derived from cadaversAccidental cuts during autopsies or surgeries
Bovine Variant of CJDBSE re-emerged in 1996 with progressive neurodegenerative disease resulting in patient deathNormally bovine but crossed to humans as Mad Cow DiseaseDiagnosis
Biopsy of BrainSpongiform encephalopathyAccumulation of abnormally folded protein
Sporadic diseaseCSF- no cells
CNS InfectionsThis was by no means a complete inventory of infectious agents involvedThere are many more however we discussed ONLY the very common and frequent infectionsThe original Mad Cow
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
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983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983091
Enterobacteriaceae
Escherichia coli K1Gram negative facultative anaerobesDuring pregnancy increased colonization of K1 strain with 8 mortality
Spreads from nasopharynx to the meningesEnterobacteriaceae Symptoms
lt1 month old- irritability lethargy vomiting lack of appetite and seizures4-18 months- nuchal rigidity tense fontanels and feverOlder children amp adults- headache vomiting confusion lethargy seizures and feve
Interactions during meningitis
Escherichia coli GI respiratory orgenitourinary tract
bloodstream
Slide kindly provided by Dr J Rayner
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 1422
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983092
Klebsiella pneumoniaeGram negative rodsHigh incidence in cockroach infested areasEarly onset- lt3 days- 2nd only to GBS
(leukopenia and neutropenia)Late onset- 8-28 days-2nd only to Staphylococcus
(leukocytosis and neutrophilia)Symptoms
Lethargy poor feeding little cry fever scleremaCulture from blood CSF urineC-reactive protein positive
Listeria monocytogenesGram positive non spore forming aerobic motile rodsEpidemiology
Food-borne (dairy and deli)Soil water decaying vegetation
Human intestines may be reservoir
2-12 humans carry the organismCan be transmitted to the baby during delivery (may cause spontaneous abortions)Pathogenesis
Grows in macrophagesReleases ldquoInternalinrdquo- as a cell attachment molecule trigger entryListeriolysin- protein that helps in movement within the cellHemolysin- pore-forming toxin Allows escape from phagosome to the phagosoleUses host cell actin to move to the new cells
DiagnosisIntracellular gram positive rods in macrophages and neutrophilsCSF culture- looks like β-Strep but catalase + and ldquotumblerdquo
Slide is kindly provided by Dr Rayner
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 1522
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983093
Spirochetes Infections of CNSTreponema pallidum
Early stages are infectious and no CNS involvementTakes about 10 year or longer for non treated cases
Neurosyphilis is the Tertiary stage of the disease and no longer infectiousDelayed hypersensitivity is part of the pathologic mechanism of tissue damageCommonly found in different tissues of the body as ldquoGummasrdquoInfection of CNS is via meningovascular routeSpirochetes Infections of CNSSymptoms
CNS degenerative changes resulting in mental changesMay have frank psychosisShuffling gait ldquotabes dorsalisrdquo
DiagnosisSpinal fluid may be helpfulElevated WBCs and protein
VDRL positive
Leptospira interogans Animals are reservoirsSpreads through animal urine contaminated water and food (survives weeks in water)No body of water in the US is free from itSensitive to Acid pH drying and soap~100 casesyearSewer workers miners veterinarians and meat packers are at risk Spirochetes Infections of CNSSymptoms
Incubation 7-13 days (range 5 days - 4 weeks)
Bacteremic phase- influenza like symptoms and fever (bacteria NOW enter the CNS)2 nd Phase - ~3+weeksHeadache with ldquoasepticrdquo meningitisSometimes hemodynamic collapse
DiagnosisBlood cultureCSF analysis and cultureRise in antibody between acute and convalescent stages
Borrelia burgdorferi~15 Neurologic abnormalities rarely fatal
Starts with a tick biteLarge spirochetes- 02x10-30 micromSpirochetes Infections of CNS
SymptomsClassic ldquobullrsquos eyerdquo rash fever joint pain meningeal irritation2nd Stage- dissemination system wide3rd Stage- mild neurologic or frank encephalitis
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 1622
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983094
DiagnosisLoose irregular spirals Silver or immunoflourescent stainDifficult to cultureCDC recommends antibody screen using ELISA
Fungal Infections of CNSDisseminate hematogenously from a remote site of infection (oropharynx or lung)Create multiple areas of infection within brain and other organsCan cause abscessesMeningoencephalitis occurs early by vascular invasion by fungusCan see secondary thrombosis cerebral infarction and hemorrhages
Common fungiCandida albicansCryptococcus neoformansHistoplasma capsulatumAspergillus fumigatus
DiagnosisAntibody studiesCXRCandida- forms granulomatus reaction Yeast forms seen with silver stainCryptococcus- fungi appear like encapsulated spheres Capsules can be seen bymucicarmine stain Histoplasma- CT scan Aspergillus- branching hyphae classical appearance
Please revisit your notes on Respiratory fungal infections by Dr Lennon
Encephalitis
EtiologyViral
Herpes viruses enteroviruses arboviruses rabies virus HIV HTLV-1Paramyxoviruses (mumps rubeola virus and arenaviruses)
Bacterial (RARE)Exceptions Legionella pneumoniae Borrelia burgdorferi Treponema pallidum
FungalCryptococcus neoformans
ParasiticPlasmodium falciparum Trypanosomes
MyelitisAcute inflammation of the spinal cord
Depending upon virus this can lead to flaccid paralysisSymptoms
HeadacheFeverIrritation followed by
Weakness of one or more extremitiesEtiology
Poliovirus was the leading cause before vaccinationWest Nile virus is the most significant after 2000
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
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983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983095
Defined as inflammation of brain parenchymaEncephalitis is considered clinically a more severe syndrome than viral meningitisSymptoms
HeadacheFever
Altered consciousness-lethargy to confusion and comaBehavioral and speech disturbanceSeizures
Arboviruses Arthropod-borne viral infectionsDistributed worldwideTransmitted by mosquitoes and ticksSporadic and epidemic encephalitisSeizures are generally the complications in children
All arboviruses are enveloped viruses with icosahedral nucleocapsid and contain a transfecting RNA
Major families of arboviruses (Togaviridae and Flaviviridae )Togaviridae
Belongs to Baltimore Class IVbEarly and late proteins madeVirus buds at the plasma membrane
TogaviridaeVenezuelan Equine Encephalitis (VEE)Togaviridae (alphavirus)
Spread through Culex and Aedes mosquitoesSymptoms
Prodrome- fever chills weakness headache myalgia (due to viral replication )Rapid progression- nuchal rigidity confusion somnolence seizure in 50 of cases andcoma (due to spread through microvascular permeability of brain then cell-to-celloccurs via axon and dendrites )NO DEATHS in humans 80 mortality in horses
Eastern Equine Encephalitis (EEE)Common in North AmericaSpreads through Aedes and Culiseta spHumans are dead-end hosts but Aedes may spread from horse to human
Clinical symptoms similar to that of VEEHIGH MORTALITY in humans
Western Equine Encephalitis (WEE)Spreads through Culex and CulisetaCommon in rural areas of US in summer monthsFatality rate 3-4 death in 1-2 days Children have a 30 chance of CNS sequelae
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
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983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983096
Pathophysiology of Equine EncephalitidesDefuse CNS involvementNeutrophils and macrophages infiltrate brain parenchyma causing focal necrosis and spottydemyelinationVascular inflammation with endothelial proliferation and small vessel thrombosis
EEELarge number of active virus entering in brain parenchymaEffects the perikaryon and dendrites of neurons with minimal glial cell infiltration
WEEDamage mediated by large number of immunologically active cells that enterbrainCell death by apoptosis primarily in the glial and inflammatory cells
FlaviviridaeBelongs to Baltimore class IVaPolyprotein is translated first which cleaves into many individual proteinsVirus buds inside cytoplasmic vesicles and the virus is released through
exocytosis
St Louis Encephalitis virus (SLE)Epidemiology
Transmitted by culex mosquitoesOvert infection depends upon
Efficiency of replication at extra neural sitesDegree of viremiaAge of the host
PathophysiologyVirus enters through BBB (astrocyte complex)
Or cross fenestrated endothelium (choroid plexus)Symptoms
Mortality 2-20 (higher in elderly)Malaise and fever only 20 develop sequelae (irritability memory loss movementdisorders motor deficits)Seizures and coma COMMONNo chronic illness
Japanese B Encephalitis virus (JBE)Epidemiology
Spread through Culex mosquitoesIncubation 4-14 days
Rural areas of AsiaSeptember 2010 India 319 deaths and Nepal 5 deaths
SymptomsViral prodrome- fever by 2nd weekEncephalitis syndrome with tremors NOT seizuresLow CSF IgGIgM ratio= higher death rate
West Nile Encephalitis virus (WNV)Epidemiology
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
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983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983097
Wild birds are reservoir spreads through Aedes mosquitoes3-15 fatalVery RARE person to person transmission
SymptomsViral prodrome with maculopapular rash on trunk and extremitiesHeadache HIGH fever nuchal rigidity stupor tremor and seizures paralysis
BunyaviridaeAt least 200 different viruses included in this groupEnveloped viruses containing single-stranded negative polarity segmented (3) RNASpreads through mosquitoes ticks and flies
California Encephalitis virusLa Crosse virus
RhabdoviridaeLyssavirus RabiesStructure
Bullet shaped virusSingle-stranded negative polarity RNA
Helical nucleocapsid in an envelope5 proteins- NPMG and L
Surface glycoprotein attaches to cell receptors including Acetylcholine receptor atneuromuscular junctions
PathophysiologyViral entry into the cell is via endocytosisVirus has a preference for nerve and salivary gland cells (travels via axons to CNS)Spreads from brain to salivary glands kidneys and conjunctival cells (virus in tears )
EpidemiologyEstimated 35000-50000 cases worldwide
Highest in Asia ~90 casesEndozoonotic all warm blooded animals are susceptible
Urban- dogs and catsSylvatic- wildlife
SymptomsIncubation 20-90 days may extend to a yearNonspecific ndash general malaise fever headache (tingling pain and weakness at the bitsite)Progressive - neurologic symptoms including insomnia confusion slight or partialparalysis agitation hypersalivation dysphagia (hydrophobia)Paralytic ndashdisorientation stupor
Death within days after symptoms (~7 days)Diagnosis
Saliva- virus isolation RT-PCRSerum and CSF for rabies antibodies (FA and ELISA)Brain tissue- Negri bodies Babes nodules consisting of glial cells
TreatmentPrevention
Wash all wounds with soap and water
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2022
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983088
1 dose of immune globulin and 4 doses of vaccine on days 137 amp14 days + 2boosters on days 0 and 3
New recommendations by CDC published on Mar 18 2010
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010(MMWR VOL59RR2 MAR 18 2010)
NOT PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent (eg povidine-iodinesolution) should be used to irrigate the wounds
Human rabies
immune globulin(HRIG)
Administer 20 IUkg body weight If anatomicallyfeasible the full dose should be infiltrated around and
into the wound(s) and any remaining volume shouldbe administered at an anatomical site (intramuscular
[IM]) distant from vaccine administration
Vaccine Human diploid cell vaccine (HDCV) or purified chickembryo cell vaccine (PCECV) 10 mL IM (deltoid but
never in the gluteal region) 1 each on days 0 3 7 and
14(For immunocompromised 5 shots)
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010
(MMWR VOL59RR2 MAR 18 2010)
PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent such as povidine-iodinesolution should be used to irrigate the wounds
HRIG HRIG should not be administered
Vaccine HDCV or PCECV 10 mL IM (deltoid but never in the
gluteal area) 1 each on days 0 and 3
For persons with immunosuppression rabies PEPshould be administered using all 5 doses of vaccine on
days 0 3 7 14 and 28
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2122
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983089
Other virus infections of the CNSArenaviridae - Lymphocytic ChoriomeningitisTogaviridae- Rubella virusHerpesviridae - Human Herpes virus 1-8Retroviridae - HIV-1Other virus infections of the CNS
Papovaviridae - Polyoma virus (JC virus)-PML (Progressive Multifocal Leukoencephalopathy)Viral DNA in majority of healthy humansMultifocal signs including hemiparesis visual loss seizures dementia personalitychanges and gait problemsCharacteristic white matter lesions common in posterior occipital area
Paramyxoviridae - Mumps viruses and Measles- SSPE (Subacute Sclerosing Pan Encephalitis)Slow fatal condition after more than 10 years of measlesWorldwide more common in boys (31) than girlsBehavior changes in school age childrenFulminant course- 10 of cases death in 3 monthsChronic course- death in 4-10 years
Brain Abscess and EmpyemaLocalized bacterial infection of brain parenchyma and subdural or epidural spacesPressure from accumulation of exudates may permanently damage the brain tissueMay be fatal if not treated properlyAbscess
Fixed boundariesEmpyema
Lack of definable shape or sizeBrain Abscess
Symptoms
Usually are rapid and associated with their locationHeadacheChanges in mental status- drowsiness to comaGeneralized seizure
Fungal brain abscessDisseminated hematogenously from remote site ( lungs or oropharynx)Create multiple areas of infection within brainMeningoencephalitis occurs early by vascular invasionEtiology
Aspergillus Cryptococcus Candida
Transmissible Spongiform EncephalopathiesPrion is an abnormal isomer of normal host proteinNO NUCLEIC ACID presentReplicate without provoking antibody or inflammatory responseAre resistant to some inactivation methods used for bacteria and viruses (70 alcohol X-raysand UV light etc)Sensitive to autoclaving and bleachDisease confined to the CNS and may take decades to manifestCan be inherited (~15) of cases)
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2222
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983090
PathogenesisNormal PrPc- glycoprotein with secondary structures dominated by Alpha helixPrion protein PrPSc- glycoprotein with secondary structures dominated by Beta-pleats When PrPSc molecules comes in contact with the normal PrPc molecule the normal PrPc changes into the abnormal PrPSc
Modified protein aggregates in neurons as myeloid plaques
Spongy appearance of cerebrum is due to the formation of vacuoles in the cortex andcerebellum
Spread of PrionsSporadic- no apparent causeInherited - through autosomal dominant traitIngestion - infected food cannibalism
Kuru-incubation ~20 yearsInvolves progressive trunchal shaking and unsteady gait Death within 3-24 months
Medical events- (Iatrogenic) through surgery organs etc
Creutzfeld Jekob Disease (CJD)Most common prion human diseasePeak incidence 55-65 years but can affect teenagersNo treatmentSymptoms
Insidious mental deteriorationEarly cerebellar and visual problemsSevere dementia in 6 monthsBrain and lower motor neuron involvementCases of CJD have been due to
Infected corneal transplantsReused improperly sterilized brain surgery equipment
Pituitary hormone injections derived from cadaversAccidental cuts during autopsies or surgeries
Bovine Variant of CJDBSE re-emerged in 1996 with progressive neurodegenerative disease resulting in patient deathNormally bovine but crossed to humans as Mad Cow DiseaseDiagnosis
Biopsy of BrainSpongiform encephalopathyAccumulation of abnormally folded protein
Sporadic diseaseCSF- no cells
CNS InfectionsThis was by no means a complete inventory of infectious agents involvedThere are many more however we discussed ONLY the very common and frequent infectionsThe original Mad Cow
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 1422
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983092
Klebsiella pneumoniaeGram negative rodsHigh incidence in cockroach infested areasEarly onset- lt3 days- 2nd only to GBS
(leukopenia and neutropenia)Late onset- 8-28 days-2nd only to Staphylococcus
(leukocytosis and neutrophilia)Symptoms
Lethargy poor feeding little cry fever scleremaCulture from blood CSF urineC-reactive protein positive
Listeria monocytogenesGram positive non spore forming aerobic motile rodsEpidemiology
Food-borne (dairy and deli)Soil water decaying vegetation
Human intestines may be reservoir
2-12 humans carry the organismCan be transmitted to the baby during delivery (may cause spontaneous abortions)Pathogenesis
Grows in macrophagesReleases ldquoInternalinrdquo- as a cell attachment molecule trigger entryListeriolysin- protein that helps in movement within the cellHemolysin- pore-forming toxin Allows escape from phagosome to the phagosoleUses host cell actin to move to the new cells
DiagnosisIntracellular gram positive rods in macrophages and neutrophilsCSF culture- looks like β-Strep but catalase + and ldquotumblerdquo
Slide is kindly provided by Dr Rayner
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 1522
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983093
Spirochetes Infections of CNSTreponema pallidum
Early stages are infectious and no CNS involvementTakes about 10 year or longer for non treated cases
Neurosyphilis is the Tertiary stage of the disease and no longer infectiousDelayed hypersensitivity is part of the pathologic mechanism of tissue damageCommonly found in different tissues of the body as ldquoGummasrdquoInfection of CNS is via meningovascular routeSpirochetes Infections of CNSSymptoms
CNS degenerative changes resulting in mental changesMay have frank psychosisShuffling gait ldquotabes dorsalisrdquo
DiagnosisSpinal fluid may be helpfulElevated WBCs and protein
VDRL positive
Leptospira interogans Animals are reservoirsSpreads through animal urine contaminated water and food (survives weeks in water)No body of water in the US is free from itSensitive to Acid pH drying and soap~100 casesyearSewer workers miners veterinarians and meat packers are at risk Spirochetes Infections of CNSSymptoms
Incubation 7-13 days (range 5 days - 4 weeks)
Bacteremic phase- influenza like symptoms and fever (bacteria NOW enter the CNS)2 nd Phase - ~3+weeksHeadache with ldquoasepticrdquo meningitisSometimes hemodynamic collapse
DiagnosisBlood cultureCSF analysis and cultureRise in antibody between acute and convalescent stages
Borrelia burgdorferi~15 Neurologic abnormalities rarely fatal
Starts with a tick biteLarge spirochetes- 02x10-30 micromSpirochetes Infections of CNS
SymptomsClassic ldquobullrsquos eyerdquo rash fever joint pain meningeal irritation2nd Stage- dissemination system wide3rd Stage- mild neurologic or frank encephalitis
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 1622
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983094
DiagnosisLoose irregular spirals Silver or immunoflourescent stainDifficult to cultureCDC recommends antibody screen using ELISA
Fungal Infections of CNSDisseminate hematogenously from a remote site of infection (oropharynx or lung)Create multiple areas of infection within brain and other organsCan cause abscessesMeningoencephalitis occurs early by vascular invasion by fungusCan see secondary thrombosis cerebral infarction and hemorrhages
Common fungiCandida albicansCryptococcus neoformansHistoplasma capsulatumAspergillus fumigatus
DiagnosisAntibody studiesCXRCandida- forms granulomatus reaction Yeast forms seen with silver stainCryptococcus- fungi appear like encapsulated spheres Capsules can be seen bymucicarmine stain Histoplasma- CT scan Aspergillus- branching hyphae classical appearance
Please revisit your notes on Respiratory fungal infections by Dr Lennon
Encephalitis
EtiologyViral
Herpes viruses enteroviruses arboviruses rabies virus HIV HTLV-1Paramyxoviruses (mumps rubeola virus and arenaviruses)
Bacterial (RARE)Exceptions Legionella pneumoniae Borrelia burgdorferi Treponema pallidum
FungalCryptococcus neoformans
ParasiticPlasmodium falciparum Trypanosomes
MyelitisAcute inflammation of the spinal cord
Depending upon virus this can lead to flaccid paralysisSymptoms
HeadacheFeverIrritation followed by
Weakness of one or more extremitiesEtiology
Poliovirus was the leading cause before vaccinationWest Nile virus is the most significant after 2000
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 1722
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983095
Defined as inflammation of brain parenchymaEncephalitis is considered clinically a more severe syndrome than viral meningitisSymptoms
HeadacheFever
Altered consciousness-lethargy to confusion and comaBehavioral and speech disturbanceSeizures
Arboviruses Arthropod-borne viral infectionsDistributed worldwideTransmitted by mosquitoes and ticksSporadic and epidemic encephalitisSeizures are generally the complications in children
All arboviruses are enveloped viruses with icosahedral nucleocapsid and contain a transfecting RNA
Major families of arboviruses (Togaviridae and Flaviviridae )Togaviridae
Belongs to Baltimore Class IVbEarly and late proteins madeVirus buds at the plasma membrane
TogaviridaeVenezuelan Equine Encephalitis (VEE)Togaviridae (alphavirus)
Spread through Culex and Aedes mosquitoesSymptoms
Prodrome- fever chills weakness headache myalgia (due to viral replication )Rapid progression- nuchal rigidity confusion somnolence seizure in 50 of cases andcoma (due to spread through microvascular permeability of brain then cell-to-celloccurs via axon and dendrites )NO DEATHS in humans 80 mortality in horses
Eastern Equine Encephalitis (EEE)Common in North AmericaSpreads through Aedes and Culiseta spHumans are dead-end hosts but Aedes may spread from horse to human
Clinical symptoms similar to that of VEEHIGH MORTALITY in humans
Western Equine Encephalitis (WEE)Spreads through Culex and CulisetaCommon in rural areas of US in summer monthsFatality rate 3-4 death in 1-2 days Children have a 30 chance of CNS sequelae
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 1822
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983096
Pathophysiology of Equine EncephalitidesDefuse CNS involvementNeutrophils and macrophages infiltrate brain parenchyma causing focal necrosis and spottydemyelinationVascular inflammation with endothelial proliferation and small vessel thrombosis
EEELarge number of active virus entering in brain parenchymaEffects the perikaryon and dendrites of neurons with minimal glial cell infiltration
WEEDamage mediated by large number of immunologically active cells that enterbrainCell death by apoptosis primarily in the glial and inflammatory cells
FlaviviridaeBelongs to Baltimore class IVaPolyprotein is translated first which cleaves into many individual proteinsVirus buds inside cytoplasmic vesicles and the virus is released through
exocytosis
St Louis Encephalitis virus (SLE)Epidemiology
Transmitted by culex mosquitoesOvert infection depends upon
Efficiency of replication at extra neural sitesDegree of viremiaAge of the host
PathophysiologyVirus enters through BBB (astrocyte complex)
Or cross fenestrated endothelium (choroid plexus)Symptoms
Mortality 2-20 (higher in elderly)Malaise and fever only 20 develop sequelae (irritability memory loss movementdisorders motor deficits)Seizures and coma COMMONNo chronic illness
Japanese B Encephalitis virus (JBE)Epidemiology
Spread through Culex mosquitoesIncubation 4-14 days
Rural areas of AsiaSeptember 2010 India 319 deaths and Nepal 5 deaths
SymptomsViral prodrome- fever by 2nd weekEncephalitis syndrome with tremors NOT seizuresLow CSF IgGIgM ratio= higher death rate
West Nile Encephalitis virus (WNV)Epidemiology
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 1922
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983097
Wild birds are reservoir spreads through Aedes mosquitoes3-15 fatalVery RARE person to person transmission
SymptomsViral prodrome with maculopapular rash on trunk and extremitiesHeadache HIGH fever nuchal rigidity stupor tremor and seizures paralysis
BunyaviridaeAt least 200 different viruses included in this groupEnveloped viruses containing single-stranded negative polarity segmented (3) RNASpreads through mosquitoes ticks and flies
California Encephalitis virusLa Crosse virus
RhabdoviridaeLyssavirus RabiesStructure
Bullet shaped virusSingle-stranded negative polarity RNA
Helical nucleocapsid in an envelope5 proteins- NPMG and L
Surface glycoprotein attaches to cell receptors including Acetylcholine receptor atneuromuscular junctions
PathophysiologyViral entry into the cell is via endocytosisVirus has a preference for nerve and salivary gland cells (travels via axons to CNS)Spreads from brain to salivary glands kidneys and conjunctival cells (virus in tears )
EpidemiologyEstimated 35000-50000 cases worldwide
Highest in Asia ~90 casesEndozoonotic all warm blooded animals are susceptible
Urban- dogs and catsSylvatic- wildlife
SymptomsIncubation 20-90 days may extend to a yearNonspecific ndash general malaise fever headache (tingling pain and weakness at the bitsite)Progressive - neurologic symptoms including insomnia confusion slight or partialparalysis agitation hypersalivation dysphagia (hydrophobia)Paralytic ndashdisorientation stupor
Death within days after symptoms (~7 days)Diagnosis
Saliva- virus isolation RT-PCRSerum and CSF for rabies antibodies (FA and ELISA)Brain tissue- Negri bodies Babes nodules consisting of glial cells
TreatmentPrevention
Wash all wounds with soap and water
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2022
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983088
1 dose of immune globulin and 4 doses of vaccine on days 137 amp14 days + 2boosters on days 0 and 3
New recommendations by CDC published on Mar 18 2010
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010(MMWR VOL59RR2 MAR 18 2010)
NOT PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent (eg povidine-iodinesolution) should be used to irrigate the wounds
Human rabies
immune globulin(HRIG)
Administer 20 IUkg body weight If anatomicallyfeasible the full dose should be infiltrated around and
into the wound(s) and any remaining volume shouldbe administered at an anatomical site (intramuscular
[IM]) distant from vaccine administration
Vaccine Human diploid cell vaccine (HDCV) or purified chickembryo cell vaccine (PCECV) 10 mL IM (deltoid but
never in the gluteal region) 1 each on days 0 3 7 and
14(For immunocompromised 5 shots)
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010
(MMWR VOL59RR2 MAR 18 2010)
PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent such as povidine-iodinesolution should be used to irrigate the wounds
HRIG HRIG should not be administered
Vaccine HDCV or PCECV 10 mL IM (deltoid but never in the
gluteal area) 1 each on days 0 and 3
For persons with immunosuppression rabies PEPshould be administered using all 5 doses of vaccine on
days 0 3 7 14 and 28
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2122
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983089
Other virus infections of the CNSArenaviridae - Lymphocytic ChoriomeningitisTogaviridae- Rubella virusHerpesviridae - Human Herpes virus 1-8Retroviridae - HIV-1Other virus infections of the CNS
Papovaviridae - Polyoma virus (JC virus)-PML (Progressive Multifocal Leukoencephalopathy)Viral DNA in majority of healthy humansMultifocal signs including hemiparesis visual loss seizures dementia personalitychanges and gait problemsCharacteristic white matter lesions common in posterior occipital area
Paramyxoviridae - Mumps viruses and Measles- SSPE (Subacute Sclerosing Pan Encephalitis)Slow fatal condition after more than 10 years of measlesWorldwide more common in boys (31) than girlsBehavior changes in school age childrenFulminant course- 10 of cases death in 3 monthsChronic course- death in 4-10 years
Brain Abscess and EmpyemaLocalized bacterial infection of brain parenchyma and subdural or epidural spacesPressure from accumulation of exudates may permanently damage the brain tissueMay be fatal if not treated properlyAbscess
Fixed boundariesEmpyema
Lack of definable shape or sizeBrain Abscess
Symptoms
Usually are rapid and associated with their locationHeadacheChanges in mental status- drowsiness to comaGeneralized seizure
Fungal brain abscessDisseminated hematogenously from remote site ( lungs or oropharynx)Create multiple areas of infection within brainMeningoencephalitis occurs early by vascular invasionEtiology
Aspergillus Cryptococcus Candida
Transmissible Spongiform EncephalopathiesPrion is an abnormal isomer of normal host proteinNO NUCLEIC ACID presentReplicate without provoking antibody or inflammatory responseAre resistant to some inactivation methods used for bacteria and viruses (70 alcohol X-raysand UV light etc)Sensitive to autoclaving and bleachDisease confined to the CNS and may take decades to manifestCan be inherited (~15) of cases)
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2222
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983090
PathogenesisNormal PrPc- glycoprotein with secondary structures dominated by Alpha helixPrion protein PrPSc- glycoprotein with secondary structures dominated by Beta-pleats When PrPSc molecules comes in contact with the normal PrPc molecule the normal PrPc changes into the abnormal PrPSc
Modified protein aggregates in neurons as myeloid plaques
Spongy appearance of cerebrum is due to the formation of vacuoles in the cortex andcerebellum
Spread of PrionsSporadic- no apparent causeInherited - through autosomal dominant traitIngestion - infected food cannibalism
Kuru-incubation ~20 yearsInvolves progressive trunchal shaking and unsteady gait Death within 3-24 months
Medical events- (Iatrogenic) through surgery organs etc
Creutzfeld Jekob Disease (CJD)Most common prion human diseasePeak incidence 55-65 years but can affect teenagersNo treatmentSymptoms
Insidious mental deteriorationEarly cerebellar and visual problemsSevere dementia in 6 monthsBrain and lower motor neuron involvementCases of CJD have been due to
Infected corneal transplantsReused improperly sterilized brain surgery equipment
Pituitary hormone injections derived from cadaversAccidental cuts during autopsies or surgeries
Bovine Variant of CJDBSE re-emerged in 1996 with progressive neurodegenerative disease resulting in patient deathNormally bovine but crossed to humans as Mad Cow DiseaseDiagnosis
Biopsy of BrainSpongiform encephalopathyAccumulation of abnormally folded protein
Sporadic diseaseCSF- no cells
CNS InfectionsThis was by no means a complete inventory of infectious agents involvedThere are many more however we discussed ONLY the very common and frequent infectionsThe original Mad Cow
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 1522
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983093
Spirochetes Infections of CNSTreponema pallidum
Early stages are infectious and no CNS involvementTakes about 10 year or longer for non treated cases
Neurosyphilis is the Tertiary stage of the disease and no longer infectiousDelayed hypersensitivity is part of the pathologic mechanism of tissue damageCommonly found in different tissues of the body as ldquoGummasrdquoInfection of CNS is via meningovascular routeSpirochetes Infections of CNSSymptoms
CNS degenerative changes resulting in mental changesMay have frank psychosisShuffling gait ldquotabes dorsalisrdquo
DiagnosisSpinal fluid may be helpfulElevated WBCs and protein
VDRL positive
Leptospira interogans Animals are reservoirsSpreads through animal urine contaminated water and food (survives weeks in water)No body of water in the US is free from itSensitive to Acid pH drying and soap~100 casesyearSewer workers miners veterinarians and meat packers are at risk Spirochetes Infections of CNSSymptoms
Incubation 7-13 days (range 5 days - 4 weeks)
Bacteremic phase- influenza like symptoms and fever (bacteria NOW enter the CNS)2 nd Phase - ~3+weeksHeadache with ldquoasepticrdquo meningitisSometimes hemodynamic collapse
DiagnosisBlood cultureCSF analysis and cultureRise in antibody between acute and convalescent stages
Borrelia burgdorferi~15 Neurologic abnormalities rarely fatal
Starts with a tick biteLarge spirochetes- 02x10-30 micromSpirochetes Infections of CNS
SymptomsClassic ldquobullrsquos eyerdquo rash fever joint pain meningeal irritation2nd Stage- dissemination system wide3rd Stage- mild neurologic or frank encephalitis
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 1622
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983094
DiagnosisLoose irregular spirals Silver or immunoflourescent stainDifficult to cultureCDC recommends antibody screen using ELISA
Fungal Infections of CNSDisseminate hematogenously from a remote site of infection (oropharynx or lung)Create multiple areas of infection within brain and other organsCan cause abscessesMeningoencephalitis occurs early by vascular invasion by fungusCan see secondary thrombosis cerebral infarction and hemorrhages
Common fungiCandida albicansCryptococcus neoformansHistoplasma capsulatumAspergillus fumigatus
DiagnosisAntibody studiesCXRCandida- forms granulomatus reaction Yeast forms seen with silver stainCryptococcus- fungi appear like encapsulated spheres Capsules can be seen bymucicarmine stain Histoplasma- CT scan Aspergillus- branching hyphae classical appearance
Please revisit your notes on Respiratory fungal infections by Dr Lennon
Encephalitis
EtiologyViral
Herpes viruses enteroviruses arboviruses rabies virus HIV HTLV-1Paramyxoviruses (mumps rubeola virus and arenaviruses)
Bacterial (RARE)Exceptions Legionella pneumoniae Borrelia burgdorferi Treponema pallidum
FungalCryptococcus neoformans
ParasiticPlasmodium falciparum Trypanosomes
MyelitisAcute inflammation of the spinal cord
Depending upon virus this can lead to flaccid paralysisSymptoms
HeadacheFeverIrritation followed by
Weakness of one or more extremitiesEtiology
Poliovirus was the leading cause before vaccinationWest Nile virus is the most significant after 2000
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 1722
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983095
Defined as inflammation of brain parenchymaEncephalitis is considered clinically a more severe syndrome than viral meningitisSymptoms
HeadacheFever
Altered consciousness-lethargy to confusion and comaBehavioral and speech disturbanceSeizures
Arboviruses Arthropod-borne viral infectionsDistributed worldwideTransmitted by mosquitoes and ticksSporadic and epidemic encephalitisSeizures are generally the complications in children
All arboviruses are enveloped viruses with icosahedral nucleocapsid and contain a transfecting RNA
Major families of arboviruses (Togaviridae and Flaviviridae )Togaviridae
Belongs to Baltimore Class IVbEarly and late proteins madeVirus buds at the plasma membrane
TogaviridaeVenezuelan Equine Encephalitis (VEE)Togaviridae (alphavirus)
Spread through Culex and Aedes mosquitoesSymptoms
Prodrome- fever chills weakness headache myalgia (due to viral replication )Rapid progression- nuchal rigidity confusion somnolence seizure in 50 of cases andcoma (due to spread through microvascular permeability of brain then cell-to-celloccurs via axon and dendrites )NO DEATHS in humans 80 mortality in horses
Eastern Equine Encephalitis (EEE)Common in North AmericaSpreads through Aedes and Culiseta spHumans are dead-end hosts but Aedes may spread from horse to human
Clinical symptoms similar to that of VEEHIGH MORTALITY in humans
Western Equine Encephalitis (WEE)Spreads through Culex and CulisetaCommon in rural areas of US in summer monthsFatality rate 3-4 death in 1-2 days Children have a 30 chance of CNS sequelae
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 1822
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983096
Pathophysiology of Equine EncephalitidesDefuse CNS involvementNeutrophils and macrophages infiltrate brain parenchyma causing focal necrosis and spottydemyelinationVascular inflammation with endothelial proliferation and small vessel thrombosis
EEELarge number of active virus entering in brain parenchymaEffects the perikaryon and dendrites of neurons with minimal glial cell infiltration
WEEDamage mediated by large number of immunologically active cells that enterbrainCell death by apoptosis primarily in the glial and inflammatory cells
FlaviviridaeBelongs to Baltimore class IVaPolyprotein is translated first which cleaves into many individual proteinsVirus buds inside cytoplasmic vesicles and the virus is released through
exocytosis
St Louis Encephalitis virus (SLE)Epidemiology
Transmitted by culex mosquitoesOvert infection depends upon
Efficiency of replication at extra neural sitesDegree of viremiaAge of the host
PathophysiologyVirus enters through BBB (astrocyte complex)
Or cross fenestrated endothelium (choroid plexus)Symptoms
Mortality 2-20 (higher in elderly)Malaise and fever only 20 develop sequelae (irritability memory loss movementdisorders motor deficits)Seizures and coma COMMONNo chronic illness
Japanese B Encephalitis virus (JBE)Epidemiology
Spread through Culex mosquitoesIncubation 4-14 days
Rural areas of AsiaSeptember 2010 India 319 deaths and Nepal 5 deaths
SymptomsViral prodrome- fever by 2nd weekEncephalitis syndrome with tremors NOT seizuresLow CSF IgGIgM ratio= higher death rate
West Nile Encephalitis virus (WNV)Epidemiology
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 1922
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983097
Wild birds are reservoir spreads through Aedes mosquitoes3-15 fatalVery RARE person to person transmission
SymptomsViral prodrome with maculopapular rash on trunk and extremitiesHeadache HIGH fever nuchal rigidity stupor tremor and seizures paralysis
BunyaviridaeAt least 200 different viruses included in this groupEnveloped viruses containing single-stranded negative polarity segmented (3) RNASpreads through mosquitoes ticks and flies
California Encephalitis virusLa Crosse virus
RhabdoviridaeLyssavirus RabiesStructure
Bullet shaped virusSingle-stranded negative polarity RNA
Helical nucleocapsid in an envelope5 proteins- NPMG and L
Surface glycoprotein attaches to cell receptors including Acetylcholine receptor atneuromuscular junctions
PathophysiologyViral entry into the cell is via endocytosisVirus has a preference for nerve and salivary gland cells (travels via axons to CNS)Spreads from brain to salivary glands kidneys and conjunctival cells (virus in tears )
EpidemiologyEstimated 35000-50000 cases worldwide
Highest in Asia ~90 casesEndozoonotic all warm blooded animals are susceptible
Urban- dogs and catsSylvatic- wildlife
SymptomsIncubation 20-90 days may extend to a yearNonspecific ndash general malaise fever headache (tingling pain and weakness at the bitsite)Progressive - neurologic symptoms including insomnia confusion slight or partialparalysis agitation hypersalivation dysphagia (hydrophobia)Paralytic ndashdisorientation stupor
Death within days after symptoms (~7 days)Diagnosis
Saliva- virus isolation RT-PCRSerum and CSF for rabies antibodies (FA and ELISA)Brain tissue- Negri bodies Babes nodules consisting of glial cells
TreatmentPrevention
Wash all wounds with soap and water
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2022
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983088
1 dose of immune globulin and 4 doses of vaccine on days 137 amp14 days + 2boosters on days 0 and 3
New recommendations by CDC published on Mar 18 2010
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010(MMWR VOL59RR2 MAR 18 2010)
NOT PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent (eg povidine-iodinesolution) should be used to irrigate the wounds
Human rabies
immune globulin(HRIG)
Administer 20 IUkg body weight If anatomicallyfeasible the full dose should be infiltrated around and
into the wound(s) and any remaining volume shouldbe administered at an anatomical site (intramuscular
[IM]) distant from vaccine administration
Vaccine Human diploid cell vaccine (HDCV) or purified chickembryo cell vaccine (PCECV) 10 mL IM (deltoid but
never in the gluteal region) 1 each on days 0 3 7 and
14(For immunocompromised 5 shots)
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010
(MMWR VOL59RR2 MAR 18 2010)
PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent such as povidine-iodinesolution should be used to irrigate the wounds
HRIG HRIG should not be administered
Vaccine HDCV or PCECV 10 mL IM (deltoid but never in the
gluteal area) 1 each on days 0 and 3
For persons with immunosuppression rabies PEPshould be administered using all 5 doses of vaccine on
days 0 3 7 14 and 28
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2122
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983089
Other virus infections of the CNSArenaviridae - Lymphocytic ChoriomeningitisTogaviridae- Rubella virusHerpesviridae - Human Herpes virus 1-8Retroviridae - HIV-1Other virus infections of the CNS
Papovaviridae - Polyoma virus (JC virus)-PML (Progressive Multifocal Leukoencephalopathy)Viral DNA in majority of healthy humansMultifocal signs including hemiparesis visual loss seizures dementia personalitychanges and gait problemsCharacteristic white matter lesions common in posterior occipital area
Paramyxoviridae - Mumps viruses and Measles- SSPE (Subacute Sclerosing Pan Encephalitis)Slow fatal condition after more than 10 years of measlesWorldwide more common in boys (31) than girlsBehavior changes in school age childrenFulminant course- 10 of cases death in 3 monthsChronic course- death in 4-10 years
Brain Abscess and EmpyemaLocalized bacterial infection of brain parenchyma and subdural or epidural spacesPressure from accumulation of exudates may permanently damage the brain tissueMay be fatal if not treated properlyAbscess
Fixed boundariesEmpyema
Lack of definable shape or sizeBrain Abscess
Symptoms
Usually are rapid and associated with their locationHeadacheChanges in mental status- drowsiness to comaGeneralized seizure
Fungal brain abscessDisseminated hematogenously from remote site ( lungs or oropharynx)Create multiple areas of infection within brainMeningoencephalitis occurs early by vascular invasionEtiology
Aspergillus Cryptococcus Candida
Transmissible Spongiform EncephalopathiesPrion is an abnormal isomer of normal host proteinNO NUCLEIC ACID presentReplicate without provoking antibody or inflammatory responseAre resistant to some inactivation methods used for bacteria and viruses (70 alcohol X-raysand UV light etc)Sensitive to autoclaving and bleachDisease confined to the CNS and may take decades to manifestCan be inherited (~15) of cases)
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2222
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983090
PathogenesisNormal PrPc- glycoprotein with secondary structures dominated by Alpha helixPrion protein PrPSc- glycoprotein with secondary structures dominated by Beta-pleats When PrPSc molecules comes in contact with the normal PrPc molecule the normal PrPc changes into the abnormal PrPSc
Modified protein aggregates in neurons as myeloid plaques
Spongy appearance of cerebrum is due to the formation of vacuoles in the cortex andcerebellum
Spread of PrionsSporadic- no apparent causeInherited - through autosomal dominant traitIngestion - infected food cannibalism
Kuru-incubation ~20 yearsInvolves progressive trunchal shaking and unsteady gait Death within 3-24 months
Medical events- (Iatrogenic) through surgery organs etc
Creutzfeld Jekob Disease (CJD)Most common prion human diseasePeak incidence 55-65 years but can affect teenagersNo treatmentSymptoms
Insidious mental deteriorationEarly cerebellar and visual problemsSevere dementia in 6 monthsBrain and lower motor neuron involvementCases of CJD have been due to
Infected corneal transplantsReused improperly sterilized brain surgery equipment
Pituitary hormone injections derived from cadaversAccidental cuts during autopsies or surgeries
Bovine Variant of CJDBSE re-emerged in 1996 with progressive neurodegenerative disease resulting in patient deathNormally bovine but crossed to humans as Mad Cow DiseaseDiagnosis
Biopsy of BrainSpongiform encephalopathyAccumulation of abnormally folded protein
Sporadic diseaseCSF- no cells
CNS InfectionsThis was by no means a complete inventory of infectious agents involvedThere are many more however we discussed ONLY the very common and frequent infectionsThe original Mad Cow
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 1622
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983094
DiagnosisLoose irregular spirals Silver or immunoflourescent stainDifficult to cultureCDC recommends antibody screen using ELISA
Fungal Infections of CNSDisseminate hematogenously from a remote site of infection (oropharynx or lung)Create multiple areas of infection within brain and other organsCan cause abscessesMeningoencephalitis occurs early by vascular invasion by fungusCan see secondary thrombosis cerebral infarction and hemorrhages
Common fungiCandida albicansCryptococcus neoformansHistoplasma capsulatumAspergillus fumigatus
DiagnosisAntibody studiesCXRCandida- forms granulomatus reaction Yeast forms seen with silver stainCryptococcus- fungi appear like encapsulated spheres Capsules can be seen bymucicarmine stain Histoplasma- CT scan Aspergillus- branching hyphae classical appearance
Please revisit your notes on Respiratory fungal infections by Dr Lennon
Encephalitis
EtiologyViral
Herpes viruses enteroviruses arboviruses rabies virus HIV HTLV-1Paramyxoviruses (mumps rubeola virus and arenaviruses)
Bacterial (RARE)Exceptions Legionella pneumoniae Borrelia burgdorferi Treponema pallidum
FungalCryptococcus neoformans
ParasiticPlasmodium falciparum Trypanosomes
MyelitisAcute inflammation of the spinal cord
Depending upon virus this can lead to flaccid paralysisSymptoms
HeadacheFeverIrritation followed by
Weakness of one or more extremitiesEtiology
Poliovirus was the leading cause before vaccinationWest Nile virus is the most significant after 2000
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 1722
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983095
Defined as inflammation of brain parenchymaEncephalitis is considered clinically a more severe syndrome than viral meningitisSymptoms
HeadacheFever
Altered consciousness-lethargy to confusion and comaBehavioral and speech disturbanceSeizures
Arboviruses Arthropod-borne viral infectionsDistributed worldwideTransmitted by mosquitoes and ticksSporadic and epidemic encephalitisSeizures are generally the complications in children
All arboviruses are enveloped viruses with icosahedral nucleocapsid and contain a transfecting RNA
Major families of arboviruses (Togaviridae and Flaviviridae )Togaviridae
Belongs to Baltimore Class IVbEarly and late proteins madeVirus buds at the plasma membrane
TogaviridaeVenezuelan Equine Encephalitis (VEE)Togaviridae (alphavirus)
Spread through Culex and Aedes mosquitoesSymptoms
Prodrome- fever chills weakness headache myalgia (due to viral replication )Rapid progression- nuchal rigidity confusion somnolence seizure in 50 of cases andcoma (due to spread through microvascular permeability of brain then cell-to-celloccurs via axon and dendrites )NO DEATHS in humans 80 mortality in horses
Eastern Equine Encephalitis (EEE)Common in North AmericaSpreads through Aedes and Culiseta spHumans are dead-end hosts but Aedes may spread from horse to human
Clinical symptoms similar to that of VEEHIGH MORTALITY in humans
Western Equine Encephalitis (WEE)Spreads through Culex and CulisetaCommon in rural areas of US in summer monthsFatality rate 3-4 death in 1-2 days Children have a 30 chance of CNS sequelae
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 1822
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983096
Pathophysiology of Equine EncephalitidesDefuse CNS involvementNeutrophils and macrophages infiltrate brain parenchyma causing focal necrosis and spottydemyelinationVascular inflammation with endothelial proliferation and small vessel thrombosis
EEELarge number of active virus entering in brain parenchymaEffects the perikaryon and dendrites of neurons with minimal glial cell infiltration
WEEDamage mediated by large number of immunologically active cells that enterbrainCell death by apoptosis primarily in the glial and inflammatory cells
FlaviviridaeBelongs to Baltimore class IVaPolyprotein is translated first which cleaves into many individual proteinsVirus buds inside cytoplasmic vesicles and the virus is released through
exocytosis
St Louis Encephalitis virus (SLE)Epidemiology
Transmitted by culex mosquitoesOvert infection depends upon
Efficiency of replication at extra neural sitesDegree of viremiaAge of the host
PathophysiologyVirus enters through BBB (astrocyte complex)
Or cross fenestrated endothelium (choroid plexus)Symptoms
Mortality 2-20 (higher in elderly)Malaise and fever only 20 develop sequelae (irritability memory loss movementdisorders motor deficits)Seizures and coma COMMONNo chronic illness
Japanese B Encephalitis virus (JBE)Epidemiology
Spread through Culex mosquitoesIncubation 4-14 days
Rural areas of AsiaSeptember 2010 India 319 deaths and Nepal 5 deaths
SymptomsViral prodrome- fever by 2nd weekEncephalitis syndrome with tremors NOT seizuresLow CSF IgGIgM ratio= higher death rate
West Nile Encephalitis virus (WNV)Epidemiology
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 1922
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983097
Wild birds are reservoir spreads through Aedes mosquitoes3-15 fatalVery RARE person to person transmission
SymptomsViral prodrome with maculopapular rash on trunk and extremitiesHeadache HIGH fever nuchal rigidity stupor tremor and seizures paralysis
BunyaviridaeAt least 200 different viruses included in this groupEnveloped viruses containing single-stranded negative polarity segmented (3) RNASpreads through mosquitoes ticks and flies
California Encephalitis virusLa Crosse virus
RhabdoviridaeLyssavirus RabiesStructure
Bullet shaped virusSingle-stranded negative polarity RNA
Helical nucleocapsid in an envelope5 proteins- NPMG and L
Surface glycoprotein attaches to cell receptors including Acetylcholine receptor atneuromuscular junctions
PathophysiologyViral entry into the cell is via endocytosisVirus has a preference for nerve and salivary gland cells (travels via axons to CNS)Spreads from brain to salivary glands kidneys and conjunctival cells (virus in tears )
EpidemiologyEstimated 35000-50000 cases worldwide
Highest in Asia ~90 casesEndozoonotic all warm blooded animals are susceptible
Urban- dogs and catsSylvatic- wildlife
SymptomsIncubation 20-90 days may extend to a yearNonspecific ndash general malaise fever headache (tingling pain and weakness at the bitsite)Progressive - neurologic symptoms including insomnia confusion slight or partialparalysis agitation hypersalivation dysphagia (hydrophobia)Paralytic ndashdisorientation stupor
Death within days after symptoms (~7 days)Diagnosis
Saliva- virus isolation RT-PCRSerum and CSF for rabies antibodies (FA and ELISA)Brain tissue- Negri bodies Babes nodules consisting of glial cells
TreatmentPrevention
Wash all wounds with soap and water
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2022
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983088
1 dose of immune globulin and 4 doses of vaccine on days 137 amp14 days + 2boosters on days 0 and 3
New recommendations by CDC published on Mar 18 2010
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010(MMWR VOL59RR2 MAR 18 2010)
NOT PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent (eg povidine-iodinesolution) should be used to irrigate the wounds
Human rabies
immune globulin(HRIG)
Administer 20 IUkg body weight If anatomicallyfeasible the full dose should be infiltrated around and
into the wound(s) and any remaining volume shouldbe administered at an anatomical site (intramuscular
[IM]) distant from vaccine administration
Vaccine Human diploid cell vaccine (HDCV) or purified chickembryo cell vaccine (PCECV) 10 mL IM (deltoid but
never in the gluteal region) 1 each on days 0 3 7 and
14(For immunocompromised 5 shots)
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010
(MMWR VOL59RR2 MAR 18 2010)
PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent such as povidine-iodinesolution should be used to irrigate the wounds
HRIG HRIG should not be administered
Vaccine HDCV or PCECV 10 mL IM (deltoid but never in the
gluteal area) 1 each on days 0 and 3
For persons with immunosuppression rabies PEPshould be administered using all 5 doses of vaccine on
days 0 3 7 14 and 28
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2122
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983089
Other virus infections of the CNSArenaviridae - Lymphocytic ChoriomeningitisTogaviridae- Rubella virusHerpesviridae - Human Herpes virus 1-8Retroviridae - HIV-1Other virus infections of the CNS
Papovaviridae - Polyoma virus (JC virus)-PML (Progressive Multifocal Leukoencephalopathy)Viral DNA in majority of healthy humansMultifocal signs including hemiparesis visual loss seizures dementia personalitychanges and gait problemsCharacteristic white matter lesions common in posterior occipital area
Paramyxoviridae - Mumps viruses and Measles- SSPE (Subacute Sclerosing Pan Encephalitis)Slow fatal condition after more than 10 years of measlesWorldwide more common in boys (31) than girlsBehavior changes in school age childrenFulminant course- 10 of cases death in 3 monthsChronic course- death in 4-10 years
Brain Abscess and EmpyemaLocalized bacterial infection of brain parenchyma and subdural or epidural spacesPressure from accumulation of exudates may permanently damage the brain tissueMay be fatal if not treated properlyAbscess
Fixed boundariesEmpyema
Lack of definable shape or sizeBrain Abscess
Symptoms
Usually are rapid and associated with their locationHeadacheChanges in mental status- drowsiness to comaGeneralized seizure
Fungal brain abscessDisseminated hematogenously from remote site ( lungs or oropharynx)Create multiple areas of infection within brainMeningoencephalitis occurs early by vascular invasionEtiology
Aspergillus Cryptococcus Candida
Transmissible Spongiform EncephalopathiesPrion is an abnormal isomer of normal host proteinNO NUCLEIC ACID presentReplicate without provoking antibody or inflammatory responseAre resistant to some inactivation methods used for bacteria and viruses (70 alcohol X-raysand UV light etc)Sensitive to autoclaving and bleachDisease confined to the CNS and may take decades to manifestCan be inherited (~15) of cases)
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2222
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983090
PathogenesisNormal PrPc- glycoprotein with secondary structures dominated by Alpha helixPrion protein PrPSc- glycoprotein with secondary structures dominated by Beta-pleats When PrPSc molecules comes in contact with the normal PrPc molecule the normal PrPc changes into the abnormal PrPSc
Modified protein aggregates in neurons as myeloid plaques
Spongy appearance of cerebrum is due to the formation of vacuoles in the cortex andcerebellum
Spread of PrionsSporadic- no apparent causeInherited - through autosomal dominant traitIngestion - infected food cannibalism
Kuru-incubation ~20 yearsInvolves progressive trunchal shaking and unsteady gait Death within 3-24 months
Medical events- (Iatrogenic) through surgery organs etc
Creutzfeld Jekob Disease (CJD)Most common prion human diseasePeak incidence 55-65 years but can affect teenagersNo treatmentSymptoms
Insidious mental deteriorationEarly cerebellar and visual problemsSevere dementia in 6 monthsBrain and lower motor neuron involvementCases of CJD have been due to
Infected corneal transplantsReused improperly sterilized brain surgery equipment
Pituitary hormone injections derived from cadaversAccidental cuts during autopsies or surgeries
Bovine Variant of CJDBSE re-emerged in 1996 with progressive neurodegenerative disease resulting in patient deathNormally bovine but crossed to humans as Mad Cow DiseaseDiagnosis
Biopsy of BrainSpongiform encephalopathyAccumulation of abnormally folded protein
Sporadic diseaseCSF- no cells
CNS InfectionsThis was by no means a complete inventory of infectious agents involvedThere are many more however we discussed ONLY the very common and frequent infectionsThe original Mad Cow
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 1722
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983095
Defined as inflammation of brain parenchymaEncephalitis is considered clinically a more severe syndrome than viral meningitisSymptoms
HeadacheFever
Altered consciousness-lethargy to confusion and comaBehavioral and speech disturbanceSeizures
Arboviruses Arthropod-borne viral infectionsDistributed worldwideTransmitted by mosquitoes and ticksSporadic and epidemic encephalitisSeizures are generally the complications in children
All arboviruses are enveloped viruses with icosahedral nucleocapsid and contain a transfecting RNA
Major families of arboviruses (Togaviridae and Flaviviridae )Togaviridae
Belongs to Baltimore Class IVbEarly and late proteins madeVirus buds at the plasma membrane
TogaviridaeVenezuelan Equine Encephalitis (VEE)Togaviridae (alphavirus)
Spread through Culex and Aedes mosquitoesSymptoms
Prodrome- fever chills weakness headache myalgia (due to viral replication )Rapid progression- nuchal rigidity confusion somnolence seizure in 50 of cases andcoma (due to spread through microvascular permeability of brain then cell-to-celloccurs via axon and dendrites )NO DEATHS in humans 80 mortality in horses
Eastern Equine Encephalitis (EEE)Common in North AmericaSpreads through Aedes and Culiseta spHumans are dead-end hosts but Aedes may spread from horse to human
Clinical symptoms similar to that of VEEHIGH MORTALITY in humans
Western Equine Encephalitis (WEE)Spreads through Culex and CulisetaCommon in rural areas of US in summer monthsFatality rate 3-4 death in 1-2 days Children have a 30 chance of CNS sequelae
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 1822
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983096
Pathophysiology of Equine EncephalitidesDefuse CNS involvementNeutrophils and macrophages infiltrate brain parenchyma causing focal necrosis and spottydemyelinationVascular inflammation with endothelial proliferation and small vessel thrombosis
EEELarge number of active virus entering in brain parenchymaEffects the perikaryon and dendrites of neurons with minimal glial cell infiltration
WEEDamage mediated by large number of immunologically active cells that enterbrainCell death by apoptosis primarily in the glial and inflammatory cells
FlaviviridaeBelongs to Baltimore class IVaPolyprotein is translated first which cleaves into many individual proteinsVirus buds inside cytoplasmic vesicles and the virus is released through
exocytosis
St Louis Encephalitis virus (SLE)Epidemiology
Transmitted by culex mosquitoesOvert infection depends upon
Efficiency of replication at extra neural sitesDegree of viremiaAge of the host
PathophysiologyVirus enters through BBB (astrocyte complex)
Or cross fenestrated endothelium (choroid plexus)Symptoms
Mortality 2-20 (higher in elderly)Malaise and fever only 20 develop sequelae (irritability memory loss movementdisorders motor deficits)Seizures and coma COMMONNo chronic illness
Japanese B Encephalitis virus (JBE)Epidemiology
Spread through Culex mosquitoesIncubation 4-14 days
Rural areas of AsiaSeptember 2010 India 319 deaths and Nepal 5 deaths
SymptomsViral prodrome- fever by 2nd weekEncephalitis syndrome with tremors NOT seizuresLow CSF IgGIgM ratio= higher death rate
West Nile Encephalitis virus (WNV)Epidemiology
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 1922
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983097
Wild birds are reservoir spreads through Aedes mosquitoes3-15 fatalVery RARE person to person transmission
SymptomsViral prodrome with maculopapular rash on trunk and extremitiesHeadache HIGH fever nuchal rigidity stupor tremor and seizures paralysis
BunyaviridaeAt least 200 different viruses included in this groupEnveloped viruses containing single-stranded negative polarity segmented (3) RNASpreads through mosquitoes ticks and flies
California Encephalitis virusLa Crosse virus
RhabdoviridaeLyssavirus RabiesStructure
Bullet shaped virusSingle-stranded negative polarity RNA
Helical nucleocapsid in an envelope5 proteins- NPMG and L
Surface glycoprotein attaches to cell receptors including Acetylcholine receptor atneuromuscular junctions
PathophysiologyViral entry into the cell is via endocytosisVirus has a preference for nerve and salivary gland cells (travels via axons to CNS)Spreads from brain to salivary glands kidneys and conjunctival cells (virus in tears )
EpidemiologyEstimated 35000-50000 cases worldwide
Highest in Asia ~90 casesEndozoonotic all warm blooded animals are susceptible
Urban- dogs and catsSylvatic- wildlife
SymptomsIncubation 20-90 days may extend to a yearNonspecific ndash general malaise fever headache (tingling pain and weakness at the bitsite)Progressive - neurologic symptoms including insomnia confusion slight or partialparalysis agitation hypersalivation dysphagia (hydrophobia)Paralytic ndashdisorientation stupor
Death within days after symptoms (~7 days)Diagnosis
Saliva- virus isolation RT-PCRSerum and CSF for rabies antibodies (FA and ELISA)Brain tissue- Negri bodies Babes nodules consisting of glial cells
TreatmentPrevention
Wash all wounds with soap and water
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2022
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983088
1 dose of immune globulin and 4 doses of vaccine on days 137 amp14 days + 2boosters on days 0 and 3
New recommendations by CDC published on Mar 18 2010
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010(MMWR VOL59RR2 MAR 18 2010)
NOT PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent (eg povidine-iodinesolution) should be used to irrigate the wounds
Human rabies
immune globulin(HRIG)
Administer 20 IUkg body weight If anatomicallyfeasible the full dose should be infiltrated around and
into the wound(s) and any remaining volume shouldbe administered at an anatomical site (intramuscular
[IM]) distant from vaccine administration
Vaccine Human diploid cell vaccine (HDCV) or purified chickembryo cell vaccine (PCECV) 10 mL IM (deltoid but
never in the gluteal region) 1 each on days 0 3 7 and
14(For immunocompromised 5 shots)
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010
(MMWR VOL59RR2 MAR 18 2010)
PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent such as povidine-iodinesolution should be used to irrigate the wounds
HRIG HRIG should not be administered
Vaccine HDCV or PCECV 10 mL IM (deltoid but never in the
gluteal area) 1 each on days 0 and 3
For persons with immunosuppression rabies PEPshould be administered using all 5 doses of vaccine on
days 0 3 7 14 and 28
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2122
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983089
Other virus infections of the CNSArenaviridae - Lymphocytic ChoriomeningitisTogaviridae- Rubella virusHerpesviridae - Human Herpes virus 1-8Retroviridae - HIV-1Other virus infections of the CNS
Papovaviridae - Polyoma virus (JC virus)-PML (Progressive Multifocal Leukoencephalopathy)Viral DNA in majority of healthy humansMultifocal signs including hemiparesis visual loss seizures dementia personalitychanges and gait problemsCharacteristic white matter lesions common in posterior occipital area
Paramyxoviridae - Mumps viruses and Measles- SSPE (Subacute Sclerosing Pan Encephalitis)Slow fatal condition after more than 10 years of measlesWorldwide more common in boys (31) than girlsBehavior changes in school age childrenFulminant course- 10 of cases death in 3 monthsChronic course- death in 4-10 years
Brain Abscess and EmpyemaLocalized bacterial infection of brain parenchyma and subdural or epidural spacesPressure from accumulation of exudates may permanently damage the brain tissueMay be fatal if not treated properlyAbscess
Fixed boundariesEmpyema
Lack of definable shape or sizeBrain Abscess
Symptoms
Usually are rapid and associated with their locationHeadacheChanges in mental status- drowsiness to comaGeneralized seizure
Fungal brain abscessDisseminated hematogenously from remote site ( lungs or oropharynx)Create multiple areas of infection within brainMeningoencephalitis occurs early by vascular invasionEtiology
Aspergillus Cryptococcus Candida
Transmissible Spongiform EncephalopathiesPrion is an abnormal isomer of normal host proteinNO NUCLEIC ACID presentReplicate without provoking antibody or inflammatory responseAre resistant to some inactivation methods used for bacteria and viruses (70 alcohol X-raysand UV light etc)Sensitive to autoclaving and bleachDisease confined to the CNS and may take decades to manifestCan be inherited (~15) of cases)
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2222
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983090
PathogenesisNormal PrPc- glycoprotein with secondary structures dominated by Alpha helixPrion protein PrPSc- glycoprotein with secondary structures dominated by Beta-pleats When PrPSc molecules comes in contact with the normal PrPc molecule the normal PrPc changes into the abnormal PrPSc
Modified protein aggregates in neurons as myeloid plaques
Spongy appearance of cerebrum is due to the formation of vacuoles in the cortex andcerebellum
Spread of PrionsSporadic- no apparent causeInherited - through autosomal dominant traitIngestion - infected food cannibalism
Kuru-incubation ~20 yearsInvolves progressive trunchal shaking and unsteady gait Death within 3-24 months
Medical events- (Iatrogenic) through surgery organs etc
Creutzfeld Jekob Disease (CJD)Most common prion human diseasePeak incidence 55-65 years but can affect teenagersNo treatmentSymptoms
Insidious mental deteriorationEarly cerebellar and visual problemsSevere dementia in 6 monthsBrain and lower motor neuron involvementCases of CJD have been due to
Infected corneal transplantsReused improperly sterilized brain surgery equipment
Pituitary hormone injections derived from cadaversAccidental cuts during autopsies or surgeries
Bovine Variant of CJDBSE re-emerged in 1996 with progressive neurodegenerative disease resulting in patient deathNormally bovine but crossed to humans as Mad Cow DiseaseDiagnosis
Biopsy of BrainSpongiform encephalopathyAccumulation of abnormally folded protein
Sporadic diseaseCSF- no cells
CNS InfectionsThis was by no means a complete inventory of infectious agents involvedThere are many more however we discussed ONLY the very common and frequent infectionsThe original Mad Cow
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 1822
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983096
Pathophysiology of Equine EncephalitidesDefuse CNS involvementNeutrophils and macrophages infiltrate brain parenchyma causing focal necrosis and spottydemyelinationVascular inflammation with endothelial proliferation and small vessel thrombosis
EEELarge number of active virus entering in brain parenchymaEffects the perikaryon and dendrites of neurons with minimal glial cell infiltration
WEEDamage mediated by large number of immunologically active cells that enterbrainCell death by apoptosis primarily in the glial and inflammatory cells
FlaviviridaeBelongs to Baltimore class IVaPolyprotein is translated first which cleaves into many individual proteinsVirus buds inside cytoplasmic vesicles and the virus is released through
exocytosis
St Louis Encephalitis virus (SLE)Epidemiology
Transmitted by culex mosquitoesOvert infection depends upon
Efficiency of replication at extra neural sitesDegree of viremiaAge of the host
PathophysiologyVirus enters through BBB (astrocyte complex)
Or cross fenestrated endothelium (choroid plexus)Symptoms
Mortality 2-20 (higher in elderly)Malaise and fever only 20 develop sequelae (irritability memory loss movementdisorders motor deficits)Seizures and coma COMMONNo chronic illness
Japanese B Encephalitis virus (JBE)Epidemiology
Spread through Culex mosquitoesIncubation 4-14 days
Rural areas of AsiaSeptember 2010 India 319 deaths and Nepal 5 deaths
SymptomsViral prodrome- fever by 2nd weekEncephalitis syndrome with tremors NOT seizuresLow CSF IgGIgM ratio= higher death rate
West Nile Encephalitis virus (WNV)Epidemiology
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 1922
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983097
Wild birds are reservoir spreads through Aedes mosquitoes3-15 fatalVery RARE person to person transmission
SymptomsViral prodrome with maculopapular rash on trunk and extremitiesHeadache HIGH fever nuchal rigidity stupor tremor and seizures paralysis
BunyaviridaeAt least 200 different viruses included in this groupEnveloped viruses containing single-stranded negative polarity segmented (3) RNASpreads through mosquitoes ticks and flies
California Encephalitis virusLa Crosse virus
RhabdoviridaeLyssavirus RabiesStructure
Bullet shaped virusSingle-stranded negative polarity RNA
Helical nucleocapsid in an envelope5 proteins- NPMG and L
Surface glycoprotein attaches to cell receptors including Acetylcholine receptor atneuromuscular junctions
PathophysiologyViral entry into the cell is via endocytosisVirus has a preference for nerve and salivary gland cells (travels via axons to CNS)Spreads from brain to salivary glands kidneys and conjunctival cells (virus in tears )
EpidemiologyEstimated 35000-50000 cases worldwide
Highest in Asia ~90 casesEndozoonotic all warm blooded animals are susceptible
Urban- dogs and catsSylvatic- wildlife
SymptomsIncubation 20-90 days may extend to a yearNonspecific ndash general malaise fever headache (tingling pain and weakness at the bitsite)Progressive - neurologic symptoms including insomnia confusion slight or partialparalysis agitation hypersalivation dysphagia (hydrophobia)Paralytic ndashdisorientation stupor
Death within days after symptoms (~7 days)Diagnosis
Saliva- virus isolation RT-PCRSerum and CSF for rabies antibodies (FA and ELISA)Brain tissue- Negri bodies Babes nodules consisting of glial cells
TreatmentPrevention
Wash all wounds with soap and water
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2022
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983088
1 dose of immune globulin and 4 doses of vaccine on days 137 amp14 days + 2boosters on days 0 and 3
New recommendations by CDC published on Mar 18 2010
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010(MMWR VOL59RR2 MAR 18 2010)
NOT PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent (eg povidine-iodinesolution) should be used to irrigate the wounds
Human rabies
immune globulin(HRIG)
Administer 20 IUkg body weight If anatomicallyfeasible the full dose should be infiltrated around and
into the wound(s) and any remaining volume shouldbe administered at an anatomical site (intramuscular
[IM]) distant from vaccine administration
Vaccine Human diploid cell vaccine (HDCV) or purified chickembryo cell vaccine (PCECV) 10 mL IM (deltoid but
never in the gluteal region) 1 each on days 0 3 7 and
14(For immunocompromised 5 shots)
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010
(MMWR VOL59RR2 MAR 18 2010)
PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent such as povidine-iodinesolution should be used to irrigate the wounds
HRIG HRIG should not be administered
Vaccine HDCV or PCECV 10 mL IM (deltoid but never in the
gluteal area) 1 each on days 0 and 3
For persons with immunosuppression rabies PEPshould be administered using all 5 doses of vaccine on
days 0 3 7 14 and 28
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2122
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983089
Other virus infections of the CNSArenaviridae - Lymphocytic ChoriomeningitisTogaviridae- Rubella virusHerpesviridae - Human Herpes virus 1-8Retroviridae - HIV-1Other virus infections of the CNS
Papovaviridae - Polyoma virus (JC virus)-PML (Progressive Multifocal Leukoencephalopathy)Viral DNA in majority of healthy humansMultifocal signs including hemiparesis visual loss seizures dementia personalitychanges and gait problemsCharacteristic white matter lesions common in posterior occipital area
Paramyxoviridae - Mumps viruses and Measles- SSPE (Subacute Sclerosing Pan Encephalitis)Slow fatal condition after more than 10 years of measlesWorldwide more common in boys (31) than girlsBehavior changes in school age childrenFulminant course- 10 of cases death in 3 monthsChronic course- death in 4-10 years
Brain Abscess and EmpyemaLocalized bacterial infection of brain parenchyma and subdural or epidural spacesPressure from accumulation of exudates may permanently damage the brain tissueMay be fatal if not treated properlyAbscess
Fixed boundariesEmpyema
Lack of definable shape or sizeBrain Abscess
Symptoms
Usually are rapid and associated with their locationHeadacheChanges in mental status- drowsiness to comaGeneralized seizure
Fungal brain abscessDisseminated hematogenously from remote site ( lungs or oropharynx)Create multiple areas of infection within brainMeningoencephalitis occurs early by vascular invasionEtiology
Aspergillus Cryptococcus Candida
Transmissible Spongiform EncephalopathiesPrion is an abnormal isomer of normal host proteinNO NUCLEIC ACID presentReplicate without provoking antibody or inflammatory responseAre resistant to some inactivation methods used for bacteria and viruses (70 alcohol X-raysand UV light etc)Sensitive to autoclaving and bleachDisease confined to the CNS and may take decades to manifestCan be inherited (~15) of cases)
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2222
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983090
PathogenesisNormal PrPc- glycoprotein with secondary structures dominated by Alpha helixPrion protein PrPSc- glycoprotein with secondary structures dominated by Beta-pleats When PrPSc molecules comes in contact with the normal PrPc molecule the normal PrPc changes into the abnormal PrPSc
Modified protein aggregates in neurons as myeloid plaques
Spongy appearance of cerebrum is due to the formation of vacuoles in the cortex andcerebellum
Spread of PrionsSporadic- no apparent causeInherited - through autosomal dominant traitIngestion - infected food cannibalism
Kuru-incubation ~20 yearsInvolves progressive trunchal shaking and unsteady gait Death within 3-24 months
Medical events- (Iatrogenic) through surgery organs etc
Creutzfeld Jekob Disease (CJD)Most common prion human diseasePeak incidence 55-65 years but can affect teenagersNo treatmentSymptoms
Insidious mental deteriorationEarly cerebellar and visual problemsSevere dementia in 6 monthsBrain and lower motor neuron involvementCases of CJD have been due to
Infected corneal transplantsReused improperly sterilized brain surgery equipment
Pituitary hormone injections derived from cadaversAccidental cuts during autopsies or surgeries
Bovine Variant of CJDBSE re-emerged in 1996 with progressive neurodegenerative disease resulting in patient deathNormally bovine but crossed to humans as Mad Cow DiseaseDiagnosis
Biopsy of BrainSpongiform encephalopathyAccumulation of abnormally folded protein
Sporadic diseaseCSF- no cells
CNS InfectionsThis was by no means a complete inventory of infectious agents involvedThere are many more however we discussed ONLY the very common and frequent infectionsThe original Mad Cow
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 1922
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983089983097
Wild birds are reservoir spreads through Aedes mosquitoes3-15 fatalVery RARE person to person transmission
SymptomsViral prodrome with maculopapular rash on trunk and extremitiesHeadache HIGH fever nuchal rigidity stupor tremor and seizures paralysis
BunyaviridaeAt least 200 different viruses included in this groupEnveloped viruses containing single-stranded negative polarity segmented (3) RNASpreads through mosquitoes ticks and flies
California Encephalitis virusLa Crosse virus
RhabdoviridaeLyssavirus RabiesStructure
Bullet shaped virusSingle-stranded negative polarity RNA
Helical nucleocapsid in an envelope5 proteins- NPMG and L
Surface glycoprotein attaches to cell receptors including Acetylcholine receptor atneuromuscular junctions
PathophysiologyViral entry into the cell is via endocytosisVirus has a preference for nerve and salivary gland cells (travels via axons to CNS)Spreads from brain to salivary glands kidneys and conjunctival cells (virus in tears )
EpidemiologyEstimated 35000-50000 cases worldwide
Highest in Asia ~90 casesEndozoonotic all warm blooded animals are susceptible
Urban- dogs and catsSylvatic- wildlife
SymptomsIncubation 20-90 days may extend to a yearNonspecific ndash general malaise fever headache (tingling pain and weakness at the bitsite)Progressive - neurologic symptoms including insomnia confusion slight or partialparalysis agitation hypersalivation dysphagia (hydrophobia)Paralytic ndashdisorientation stupor
Death within days after symptoms (~7 days)Diagnosis
Saliva- virus isolation RT-PCRSerum and CSF for rabies antibodies (FA and ELISA)Brain tissue- Negri bodies Babes nodules consisting of glial cells
TreatmentPrevention
Wash all wounds with soap and water
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2022
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983088
1 dose of immune globulin and 4 doses of vaccine on days 137 amp14 days + 2boosters on days 0 and 3
New recommendations by CDC published on Mar 18 2010
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010(MMWR VOL59RR2 MAR 18 2010)
NOT PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent (eg povidine-iodinesolution) should be used to irrigate the wounds
Human rabies
immune globulin(HRIG)
Administer 20 IUkg body weight If anatomicallyfeasible the full dose should be infiltrated around and
into the wound(s) and any remaining volume shouldbe administered at an anatomical site (intramuscular
[IM]) distant from vaccine administration
Vaccine Human diploid cell vaccine (HDCV) or purified chickembryo cell vaccine (PCECV) 10 mL IM (deltoid but
never in the gluteal region) 1 each on days 0 3 7 and
14(For immunocompromised 5 shots)
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010
(MMWR VOL59RR2 MAR 18 2010)
PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent such as povidine-iodinesolution should be used to irrigate the wounds
HRIG HRIG should not be administered
Vaccine HDCV or PCECV 10 mL IM (deltoid but never in the
gluteal area) 1 each on days 0 and 3
For persons with immunosuppression rabies PEPshould be administered using all 5 doses of vaccine on
days 0 3 7 14 and 28
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2122
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983089
Other virus infections of the CNSArenaviridae - Lymphocytic ChoriomeningitisTogaviridae- Rubella virusHerpesviridae - Human Herpes virus 1-8Retroviridae - HIV-1Other virus infections of the CNS
Papovaviridae - Polyoma virus (JC virus)-PML (Progressive Multifocal Leukoencephalopathy)Viral DNA in majority of healthy humansMultifocal signs including hemiparesis visual loss seizures dementia personalitychanges and gait problemsCharacteristic white matter lesions common in posterior occipital area
Paramyxoviridae - Mumps viruses and Measles- SSPE (Subacute Sclerosing Pan Encephalitis)Slow fatal condition after more than 10 years of measlesWorldwide more common in boys (31) than girlsBehavior changes in school age childrenFulminant course- 10 of cases death in 3 monthsChronic course- death in 4-10 years
Brain Abscess and EmpyemaLocalized bacterial infection of brain parenchyma and subdural or epidural spacesPressure from accumulation of exudates may permanently damage the brain tissueMay be fatal if not treated properlyAbscess
Fixed boundariesEmpyema
Lack of definable shape or sizeBrain Abscess
Symptoms
Usually are rapid and associated with their locationHeadacheChanges in mental status- drowsiness to comaGeneralized seizure
Fungal brain abscessDisseminated hematogenously from remote site ( lungs or oropharynx)Create multiple areas of infection within brainMeningoencephalitis occurs early by vascular invasionEtiology
Aspergillus Cryptococcus Candida
Transmissible Spongiform EncephalopathiesPrion is an abnormal isomer of normal host proteinNO NUCLEIC ACID presentReplicate without provoking antibody or inflammatory responseAre resistant to some inactivation methods used for bacteria and viruses (70 alcohol X-raysand UV light etc)Sensitive to autoclaving and bleachDisease confined to the CNS and may take decades to manifestCan be inherited (~15) of cases)
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2222
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983090
PathogenesisNormal PrPc- glycoprotein with secondary structures dominated by Alpha helixPrion protein PrPSc- glycoprotein with secondary structures dominated by Beta-pleats When PrPSc molecules comes in contact with the normal PrPc molecule the normal PrPc changes into the abnormal PrPSc
Modified protein aggregates in neurons as myeloid plaques
Spongy appearance of cerebrum is due to the formation of vacuoles in the cortex andcerebellum
Spread of PrionsSporadic- no apparent causeInherited - through autosomal dominant traitIngestion - infected food cannibalism
Kuru-incubation ~20 yearsInvolves progressive trunchal shaking and unsteady gait Death within 3-24 months
Medical events- (Iatrogenic) through surgery organs etc
Creutzfeld Jekob Disease (CJD)Most common prion human diseasePeak incidence 55-65 years but can affect teenagersNo treatmentSymptoms
Insidious mental deteriorationEarly cerebellar and visual problemsSevere dementia in 6 monthsBrain and lower motor neuron involvementCases of CJD have been due to
Infected corneal transplantsReused improperly sterilized brain surgery equipment
Pituitary hormone injections derived from cadaversAccidental cuts during autopsies or surgeries
Bovine Variant of CJDBSE re-emerged in 1996 with progressive neurodegenerative disease resulting in patient deathNormally bovine but crossed to humans as Mad Cow DiseaseDiagnosis
Biopsy of BrainSpongiform encephalopathyAccumulation of abnormally folded protein
Sporadic diseaseCSF- no cells
CNS InfectionsThis was by no means a complete inventory of infectious agents involvedThere are many more however we discussed ONLY the very common and frequent infectionsThe original Mad Cow
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2022
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983088
1 dose of immune globulin and 4 doses of vaccine on days 137 amp14 days + 2boosters on days 0 and 3
New recommendations by CDC published on Mar 18 2010
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010(MMWR VOL59RR2 MAR 18 2010)
NOT PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent (eg povidine-iodinesolution) should be used to irrigate the wounds
Human rabies
immune globulin(HRIG)
Administer 20 IUkg body weight If anatomicallyfeasible the full dose should be infiltrated around and
into the wound(s) and any remaining volume shouldbe administered at an anatomical site (intramuscular
[IM]) distant from vaccine administration
Vaccine Human diploid cell vaccine (HDCV) or purified chickembryo cell vaccine (PCECV) 10 mL IM (deltoid but
never in the gluteal region) 1 each on days 0 3 7 and
14(For immunocompromised 5 shots)
RABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULERABIES POSTEXPOSURE PROPHYLAXIS (PEP) SCHEDULE - -- - US 2010US 2010US 2010US 2010
(MMWR VOL59RR2 MAR 18 2010)
PREVIOUSLY VACCINATED
Intervention Regimen
(for ALL age groups including children)
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water Ifavailable a virucidal agent such as povidine-iodinesolution should be used to irrigate the wounds
HRIG HRIG should not be administered
Vaccine HDCV or PCECV 10 mL IM (deltoid but never in the
gluteal area) 1 each on days 0 and 3
For persons with immunosuppression rabies PEPshould be administered using all 5 doses of vaccine on
days 0 3 7 14 and 28
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2122
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983089
Other virus infections of the CNSArenaviridae - Lymphocytic ChoriomeningitisTogaviridae- Rubella virusHerpesviridae - Human Herpes virus 1-8Retroviridae - HIV-1Other virus infections of the CNS
Papovaviridae - Polyoma virus (JC virus)-PML (Progressive Multifocal Leukoencephalopathy)Viral DNA in majority of healthy humansMultifocal signs including hemiparesis visual loss seizures dementia personalitychanges and gait problemsCharacteristic white matter lesions common in posterior occipital area
Paramyxoviridae - Mumps viruses and Measles- SSPE (Subacute Sclerosing Pan Encephalitis)Slow fatal condition after more than 10 years of measlesWorldwide more common in boys (31) than girlsBehavior changes in school age childrenFulminant course- 10 of cases death in 3 monthsChronic course- death in 4-10 years
Brain Abscess and EmpyemaLocalized bacterial infection of brain parenchyma and subdural or epidural spacesPressure from accumulation of exudates may permanently damage the brain tissueMay be fatal if not treated properlyAbscess
Fixed boundariesEmpyema
Lack of definable shape or sizeBrain Abscess
Symptoms
Usually are rapid and associated with their locationHeadacheChanges in mental status- drowsiness to comaGeneralized seizure
Fungal brain abscessDisseminated hematogenously from remote site ( lungs or oropharynx)Create multiple areas of infection within brainMeningoencephalitis occurs early by vascular invasionEtiology
Aspergillus Cryptococcus Candida
Transmissible Spongiform EncephalopathiesPrion is an abnormal isomer of normal host proteinNO NUCLEIC ACID presentReplicate without provoking antibody or inflammatory responseAre resistant to some inactivation methods used for bacteria and viruses (70 alcohol X-raysand UV light etc)Sensitive to autoclaving and bleachDisease confined to the CNS and may take decades to manifestCan be inherited (~15) of cases)
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2222
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983090
PathogenesisNormal PrPc- glycoprotein with secondary structures dominated by Alpha helixPrion protein PrPSc- glycoprotein with secondary structures dominated by Beta-pleats When PrPSc molecules comes in contact with the normal PrPc molecule the normal PrPc changes into the abnormal PrPSc
Modified protein aggregates in neurons as myeloid plaques
Spongy appearance of cerebrum is due to the formation of vacuoles in the cortex andcerebellum
Spread of PrionsSporadic- no apparent causeInherited - through autosomal dominant traitIngestion - infected food cannibalism
Kuru-incubation ~20 yearsInvolves progressive trunchal shaking and unsteady gait Death within 3-24 months
Medical events- (Iatrogenic) through surgery organs etc
Creutzfeld Jekob Disease (CJD)Most common prion human diseasePeak incidence 55-65 years but can affect teenagersNo treatmentSymptoms
Insidious mental deteriorationEarly cerebellar and visual problemsSevere dementia in 6 monthsBrain and lower motor neuron involvementCases of CJD have been due to
Infected corneal transplantsReused improperly sterilized brain surgery equipment
Pituitary hormone injections derived from cadaversAccidental cuts during autopsies or surgeries
Bovine Variant of CJDBSE re-emerged in 1996 with progressive neurodegenerative disease resulting in patient deathNormally bovine but crossed to humans as Mad Cow DiseaseDiagnosis
Biopsy of BrainSpongiform encephalopathyAccumulation of abnormally folded protein
Sporadic diseaseCSF- no cells
CNS InfectionsThis was by no means a complete inventory of infectious agents involvedThere are many more however we discussed ONLY the very common and frequent infectionsThe original Mad Cow
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2122
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983089
Other virus infections of the CNSArenaviridae - Lymphocytic ChoriomeningitisTogaviridae- Rubella virusHerpesviridae - Human Herpes virus 1-8Retroviridae - HIV-1Other virus infections of the CNS
Papovaviridae - Polyoma virus (JC virus)-PML (Progressive Multifocal Leukoencephalopathy)Viral DNA in majority of healthy humansMultifocal signs including hemiparesis visual loss seizures dementia personalitychanges and gait problemsCharacteristic white matter lesions common in posterior occipital area
Paramyxoviridae - Mumps viruses and Measles- SSPE (Subacute Sclerosing Pan Encephalitis)Slow fatal condition after more than 10 years of measlesWorldwide more common in boys (31) than girlsBehavior changes in school age childrenFulminant course- 10 of cases death in 3 monthsChronic course- death in 4-10 years
Brain Abscess and EmpyemaLocalized bacterial infection of brain parenchyma and subdural or epidural spacesPressure from accumulation of exudates may permanently damage the brain tissueMay be fatal if not treated properlyAbscess
Fixed boundariesEmpyema
Lack of definable shape or sizeBrain Abscess
Symptoms
Usually are rapid and associated with their locationHeadacheChanges in mental status- drowsiness to comaGeneralized seizure
Fungal brain abscessDisseminated hematogenously from remote site ( lungs or oropharynx)Create multiple areas of infection within brainMeningoencephalitis occurs early by vascular invasionEtiology
Aspergillus Cryptococcus Candida
Transmissible Spongiform EncephalopathiesPrion is an abnormal isomer of normal host proteinNO NUCLEIC ACID presentReplicate without provoking antibody or inflammatory responseAre resistant to some inactivation methods used for bacteria and viruses (70 alcohol X-raysand UV light etc)Sensitive to autoclaving and bleachDisease confined to the CNS and may take decades to manifestCan be inherited (~15) of cases)
7272019 Note+Version+Lectures+36 40+CNS+Infections+F12
httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 2222
983107983118983123 983113983150983142983141983139983156983145983151983150983155
983117983141983140 983117983145983139983154983151983093983095983088983087983105983121983087983110983089983090 983091983094983085983092983088983087 983090983090
PathogenesisNormal PrPc- glycoprotein with secondary structures dominated by Alpha helixPrion protein PrPSc- glycoprotein with secondary structures dominated by Beta-pleats When PrPSc molecules comes in contact with the normal PrPc molecule the normal PrPc changes into the abnormal PrPSc
Modified protein aggregates in neurons as myeloid plaques
Spongy appearance of cerebrum is due to the formation of vacuoles in the cortex andcerebellum
Spread of PrionsSporadic- no apparent causeInherited - through autosomal dominant traitIngestion - infected food cannibalism
Kuru-incubation ~20 yearsInvolves progressive trunchal shaking and unsteady gait Death within 3-24 months
Medical events- (Iatrogenic) through surgery organs etc
Creutzfeld Jekob Disease (CJD)Most common prion human diseasePeak incidence 55-65 years but can affect teenagersNo treatmentSymptoms
Insidious mental deteriorationEarly cerebellar and visual problemsSevere dementia in 6 monthsBrain and lower motor neuron involvementCases of CJD have been due to
Infected corneal transplantsReused improperly sterilized brain surgery equipment
Pituitary hormone injections derived from cadaversAccidental cuts during autopsies or surgeries
Bovine Variant of CJDBSE re-emerged in 1996 with progressive neurodegenerative disease resulting in patient deathNormally bovine but crossed to humans as Mad Cow DiseaseDiagnosis
Biopsy of BrainSpongiform encephalopathyAccumulation of abnormally folded protein
Sporadic diseaseCSF- no cells
CNS InfectionsThis was by no means a complete inventory of infectious agents involvedThere are many more however we discussed ONLY the very common and frequent infectionsThe original Mad Cow
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PathogenesisNormal PrPc- glycoprotein with secondary structures dominated by Alpha helixPrion protein PrPSc- glycoprotein with secondary structures dominated by Beta-pleats When PrPSc molecules comes in contact with the normal PrPc molecule the normal PrPc changes into the abnormal PrPSc
Modified protein aggregates in neurons as myeloid plaques
Spongy appearance of cerebrum is due to the formation of vacuoles in the cortex andcerebellum
Spread of PrionsSporadic- no apparent causeInherited - through autosomal dominant traitIngestion - infected food cannibalism
Kuru-incubation ~20 yearsInvolves progressive trunchal shaking and unsteady gait Death within 3-24 months
Medical events- (Iatrogenic) through surgery organs etc
Creutzfeld Jekob Disease (CJD)Most common prion human diseasePeak incidence 55-65 years but can affect teenagersNo treatmentSymptoms
Insidious mental deteriorationEarly cerebellar and visual problemsSevere dementia in 6 monthsBrain and lower motor neuron involvementCases of CJD have been due to
Infected corneal transplantsReused improperly sterilized brain surgery equipment
Pituitary hormone injections derived from cadaversAccidental cuts during autopsies or surgeries
Bovine Variant of CJDBSE re-emerged in 1996 with progressive neurodegenerative disease resulting in patient deathNormally bovine but crossed to humans as Mad Cow DiseaseDiagnosis
Biopsy of BrainSpongiform encephalopathyAccumulation of abnormally folded protein
Sporadic diseaseCSF- no cells
CNS InfectionsThis was by no means a complete inventory of infectious agents involvedThere are many more however we discussed ONLY the very common and frequent infectionsThe original Mad Cow