CNSmodule/3rd yearmedicineDrHamedAl-Zoubi

AssociateProf./DepartmentofMicrobiology

Neuroscience2/Lecture1

1. Clostridiumbotulinum

2. Clostridiumtetani

3. Priondiseases

Clostridiumbotulinum• Characteristics:

• Grampositiveanaerobicrods(appearasgramnegativeinoldcultures)

• Motilebyflagella

• SevenmaintypesA-G:A,BandEarethecommonest

• Eachsecretesantigenicallydistinctbutfunctionallysimilartoxin(verypotent)

• Growsbetterat35°Cbutsomestrainsgrowat1-5°C

Clostridiumbotulinum• Itformsspores:

• Heatresistant• Widelydistributedintheenvironment;SOIL,water,vegetable,fruitmeat,honey..

• Ovalandsubterminal

Clostridiumbotulinum

• Pathogenesis:

Neurotoxinproduction>stomachabsorption>circulation>neuromuscularjunction(NMJ)>inhibitionofacetylcholinereleaseattheNMJ>flacciddescendingmotorparalysis

Clostridiumbotulinum• Thetoxin(heatlabile):

1. Preformedinfoodthatisbadlypreservedandprocessed(hygieneandheat)>foodbornebotulism

2. Sporesingestione.gHoney>germinateinthegut>toxinproduction>infantileor(intestinal) botulism

3. Sporescontaminatingwounds(e.g fractures,drugabusers)>germinate>toxinproduction>woundbotulism

Clostridiumbotulinum• Clinically(foodborneandwoundbotulism):

ü Incubationperiod12-48hrsinfoodborne,longerinwoundbotulism(days– 2weeks)

ü Early:nausea,vomiting,weakness,dizzinessbutnofever

ü Late:doublevision,difficultyinswallowing,speakingandrespiratoryfailure(descendingmotorparalysis)

• Infantile:weakness,alteredcry,lossofappetite,lossofheadcontrol,Floppychildsyndromeandsuddeninfantdeathsyndrome

Clostridiumbotulinum• Diagnosis:

• IsolatingtheorganismortoxinfromgastricaspirAtes,bloodorstool

• DetectingToxininthefood

• n.b:toxin-antitoxinapproach?

• Alertthelab

Clostridiumbotulinumü Treatment:• Gastricwash• Antitoxin• Supportive:ICUandrespiratorysupport,• InWoundbotulinum:antitoxin+cleaninganddebridement

plusantibiotics(metronidazoleandpenicillin)toreducebacterialload

ü Prevention:• Propercookingandheatingoffood?• Avoidsuspiciouscannedfood• Properprocessing,preservationandcanningoffood• vaccine

Clostridiumtetani• Widelydistributedintheenvironmentandinthesoil• Grampositive,motileanaerobicrods(GNRinoldculture)• β-Haemolysiswhengrownonbloodagar• growwellincookedmeatbroth• Sporeforming:roundterminal(drumstick,tennisracket)

Clostridiumtetani• Producetwoplasmidcodedexotoxins:

1.Tetnospasmin:

• Neurotoxin• Heavy(binding)andlightchain(neurotoxicpart)• Oneantigenictoxin

2.Tetanolysin(haemolysin):pathogenesisnotclearlyknownbut?RBCshaemolysis

Clostridiumtetani• Pathogenesis:Localsecretionofthetoxin>bindingtothepresynaptic

neurons(heavychain)>retrogradediffusionofthelightchain

tothespinalcord>inhibitionoftheinhibitoryneurotransmitter

gammaaminobutyricacid(GABA)>lossofinhibitoryactionon

motorandautonomicneurons>uncontrolledmusclecontractions(spasms)>Spasticparalysis

Clostridiumtetani/pathogenesis

Clostridiumtetaniü Clinically(tetanus):• Modeoftransmission:

• Spores>woundcontamination(lowoxygen)>germinationtobacillithatsecretethetoxins

• Incubationperiod:3days– 3weeks

ü Source:• Infectedwoundandabscesses(~65%),whichoftenisminor(eg,

woodormetalsplinters,thorns...)• Chronicskinulcersarethesourceinapproximately5%ofcases• intheremainderofcases,noobvioussourceisidentified

(cryptogenic)

Clostridiumtetani1. Local: musclesspasmandpainat/nearinjurysite

2. Cephalic:• Followingheadtraumaforexample• Localisedpicturethatmayprogresstogeneralised• cranialnervespalsy(7th cranialnerveiscommonlyinvolved)

3. Generalised:

• Trismus (lockedjaw):maybitethetongue• Opisthotonus:flexionandadductionofthearms,clenchingof

thefists,extensionofthelowerextremities

Clostridiumtetani

Clostridiumtetani3.Generalisedcont’d:

• Risus sardonicus (sardonicgrin):abnormal,sustainedspasmofthefacialmusclesthatappearstoproducegrinningorthescornfulsmileoftetanus

• spasmisstimulatedbynoiseandlight

• thepatientisafebrile

• Meningitis,seizuresandcoma

Clostridiumtetani3.Generalisedcont’d:

• Duringtheseepisodes,patientshaveintactsensationandfeelseverepain

• Thespasmscancausefractures,tendonruptures

• Arrhythmia,tachycardiaandrespiratoryfailure

Clostridiumtetani• Otherformstetanus:

ü Infantile:

• Followingumbilicalcordcontamination• DevelopswithinthefirstweektospasticParalysisandisusually

fatalü Otogenictetanus:

• sourceisfromexternalauditorymeatus(piercing,cleaning)

ClostridiumtetaniDiagnosis:

1. Clinical(mainly):

ü Signandsymptomsü Vaccinationhistory(partofthenationalchildhoodprogram)ü Historyofatrauma

2. Woundsmearstainingandculture:mayhelp

3. Toxin-antitoxintestinmice:mainlab.line

Clostridiumtetani• Treatment:• Wounddebridement• TreatinInadarkquiteroominICU• Sedation,Musclerelaxant(e.gdiazepam)andartificialventilation

• Antibiotics:ümaybegiventokillanyvegetativeformsümetronidazole• Tetanusimmunoglobulin(TIG)singleIMdose• Vaccinateifnohistoryofvaccineorunknownorifthepatientreceivedincompletevaccinedosesinthepast

Priondiseasesproteinaceousinfectiousparticles

Mainproperties:• PrionproteinsnormallyfoundhumanbrainPrPc

Ø PrPc isproteasesensitiveandfoundoncellsurfaceØ Itsfunctionisunknown

• PriondiseasecausedbyaccumulationofabnormalprionproteincalledPrPsc

Ø Resistanttoproteaseandfoundintracellularly

• ChangeofPrPc toPrPsc canbeduetogenetic,infectiousorsporadicreasons

Priondiseases

• AccumulationofPrPsc Occursinhumanandanimalscausingspongiformencephalopathies

• Theseproteinshasnonucleicacid

• Highlyresistanttoheatanddisinfectants

• Sensitivetosodiumhydroxideand134Cmoistheatautoclave5hrs

• Noimmuneresponseisgeneratedtotheseproteins

PrionsPathology:• PrPc isenzymesensitiveandhasnotendencytoaccumulate

• whilethePrPsc istheopposite• AccumulatingPrPscistoxictothebrain>encephalopathies

• Degenerativechangesinthebraincharacterisedspongiformchanges,vacuolesandamyloid plaques

Transmission:• Ingestion• Iatrogenice.gbloodtransfusion,dura matertransplants

andsurgery(brain,tonsils,appendixandspleen)

Prions/clinically1. Sporadic:Creutzfeldt – Jakob disease:85%of

cases• SporadicduetoPrPc spontaneousgeneticmutation

• 1case/millioncase,middleageandelderly(50-70y)

• Rapidlyprogressivedementiaandmyoclonus• Deathinabout6months– 2yearsfollowingsymptomsdevelopment

Prions2.Acquired:A.NewVariantCJD(Bovinespongiformencephalopathy,madcowdisease):

• ReportedinUKin1996• Ingestionofinfectedcattles• Affectedyoungagegroup~27yearsonaverage• Symptoms:Psychiatric>cerebellarsymptoms>dementiaB.Iatrogenic:duramatterandcadavericgrowthhormonetransplants,bloodtransfusion,contaminatedinstruments....

C.Kuru:

• InNewGuineapeople• Transmittedbyeatingthevisceraandbrainsof

relatives• Afteralongincubationperiod>fatalcerebellar

syndrome• Ataxiaanddementia

3.Inherited:A.Gerstmann - Straussler – Scheinker disease:ADinheritance

• Middleagedadults• Cerebellar ataxia+spasticparaparesis• Dementialately

A. Fatalfamilialinsomnia:ADinheritance• Middleagedadults• Thalamusisheavilyinvolved• Progressiveinsomniaandmyoclonus• Dementiaisrare

Prions

Diagnosis:• Clinically:dementia,myoclonus,ataxia• EEG• MRI• Post-mortem

Treatment:Nospecifictreatment

TheEnd