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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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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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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

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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

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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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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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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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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

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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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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

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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

7272019 Note+Version+Lectures+36 40+CNS+Infections+F12

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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

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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

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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

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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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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

httpslidepdfcomreaderfullnoteversionlectures36-40cnsinfectionsf12 1322

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