CNSpathologyThirdyearmedicalstudents

DrHeyamAwad2018

Lecture1:anintroduction

CNScourse

• Thisisa7hourcourseandthetopicscoveredareimportantforyourclinicalyearsandyourworkasadoctorinanyspecialityyouchoose.Pleasegiveittheimportanceitdeserves.• Wesynchronisedthelectures’topicsbetweenalldisciplines(mainlyanatomy,physiologyandpathology)soyoucanunderstandsubjectsfullyandeasilyandweminimisedrepetitionoftopicsbetweendisciplines.• Isentthecoursesyllabus,ILOSandlecturedistribution.Pleasehavealookatthesetofamiliariseyourselfwiththecourse.• Pleasenotethefacultyisbeingverystrictwithattendancepolicy,makesureyoudon'tputyourselfintotrouble;wewillnotbeabletohelpyouwiththis.

Pathologylectures

• Asusualwewillhavetwosetsofslides;oneasapresentation,andadetailedslideforthecontentofthelectures.• Thedetailedslideswillcontainalltheinformationyouneedfortheexam.• AtthebeginningofeachslideIwilllistthelearningoutcomesofthelecture,attheendIwillputasummaryofthemainpointsyouneedtoconcentrateonaswellaspracticequestionstocheckyourunderstandingandtoknowwhattoexpectintheexam.• Theslideswillbeavailableonyourwebsiteandthetheelearningbeforethelectureday.

Lecture1:introductionILOS• AquickrevisionoftheCNSstructureincludingbrainlobesandsomeoftheirfunctions• Tounderstandtheasymmetrybetweentherightandlefthemispheres,withexamples.• Toknowthestructureandfunctionofneuronsandglialcells• Tounderstandhowneuronsandglialcellsrespondtoinjury.• Toapplytheaboveknowledgeinunderstandingbraindiseases

CNS

• TheCNSiscomposedofthebrainandthespinalcord.• Itsmainfunctionistoreceiveinformation,coordinateitandsendappropriatecommandstotherestofthebody.• CNSiscomposedofwhiteandgreymatter.• Thewhitematteriscomposedofmyelinatedaxons(myelincomposedofcellmembranesofoligodendrocytes).• Thegreymatteriscomposedoftheneuronesofthecortexandcertainnuclei.

Brainlobesthebrainiscomposedoffouranatomicallobes:frontal,occipital,temporalandparietallobes.

Cerebralcortex1.frontallobe• Containstheprimarymotorcortex:performsfinalcorticalmotorprocessing• Broca’sareaintheleftfrontallobecontrolsmotor patternofspeech,ifdamaged=expressivedysphasia=thepersonknowswhathewantstosaybutcannotexpressthem.

2.Temporallobe

• Importantforcomplexprocessingofsensoryinput• ContainsWernicke'sarea:auditory,visualandsomaticassociationscoalesceinthisarea.• Ifdamaged:inabilitytounderstandspokenorwrittenlanguage.(receptivedysphasia)

ThereareassociationsbetweenBroca’sandWernicke’sareas

3.Parietallobe

• Containshighordersensoryareas• Containsareafornamingobjects• Containsareaforprocessingofvisuallanguage=reading

4.Occipitallobe:Containsthevisualcortex

Brainasymmetry

Whyunderstandingbrainasymmetryisimportant?• Samediseaseprocessescanhavedifferentconsequencesaccordingtothesideaffected• Example:astrokeaffectingtheBroca’sareaintheleftfrontallobecanresultinexpressivedysphasia.Similarlesioninthemirrorimageareaintherightsidemightresultinnosymptomsatall.

BRAINCELLS

• TheCNScontains100billionneurons.• Italsocontains10-50timesthisnumberofglialcells.• 40%ofourgenesparticipateintheformationoftheCNS.

neuron

• IstheprincipalfunctionalunitoftheCNS.• Theyreceiveandtransmitinformation• Matureneuronscannotdivide:theyarepermanentcells• However,neuralprogenitorsarefoundinthebrainandcandivide…..???ExpansionofthesecanhelppatientswithCNSdiseases(thisisanareaofactiveresearch)

Neuralprogenitors

• Neuralprogenitorsarecellsthatarecapableofdividingalimitednumberoftimesandhavethecapacitytodifferentiateintoarestrictednumberofneuronalandglialcelltypes.• Zikavirusinfectionisassociatedwithmicrocephaly,probablythroughinfectingneuralprogenitorscausingtheirdeathandresultingindecreasedbraingrowthinembryos.

ZIKAVIRUS

• Basedonasystematicreviewoftheliteratureupto30May2016,WHOhasconcludedthatZikavirusinfectionduringpregnancyisacauseofcongenitalbrainabnormalities,includingmicrocephaly.itisthoughtthatthevirusdoessobyinfectingprogenitorcells.

Basicstructureofneurons.

Neuronscomeinseveralshapes!

GLIALcells= ةیقبدایالخ

• Aresupportivecells4types:1. Astrocytes2. Oligodendrocytes3. Microglialcells4. Ependymalcells

Astrocytes= ةیمجنایالخ

• givestructuralsupporttoneurons• controlneuralbiochemicalenvironment.• Astrocyteprocessesareassociatedwiththebloodvesselstoformthebloodbrainbarrier

Astrocytes

Oligodendrocytes= نصغتلاةلیلقةیقبد

• Oligodendrocytesformthemyelinsheathwhichsurroundsaxonsandisimportantforfasttransmissionofactionpotentialbysalutatoryconduction

Microglialcells= ةریغصلاةیقبدلاایالخلا

• Microglia:bloodderivedmacrophages

Ependymalcells ةیبصعلاةناطبلاایالخ =

• Theylinetheventricleandthespinalcord.

ReactionofneuronstoACUTE injury

• Acute neuronalinjuryformsredneurons• redneutronsresultusuallyduetoacuteinjuryduetohypoxiaorischemia.• redneuronistheearliestmorphologicmanifestationofneuronalcelldeath• Appearafter12-24hoursofirreversible injury• Characterisedmicroscopicallybyshrinkageofcellbody,pyknosis,disappearanceofthenucleolusandLossofNisslsubstance(seenextslidefordefinition)• lossofNisslsubstanceresultsinintensecytoplasmiceosinophilia

• Nisslsubstance:largegranularsubstancefoundinneurons.Thesegranules areofroughendoplasmicreticulum(RER)withrosettesoffreeribosomes,andarethesiteofproteinsynthesis.

Redneurons

Redneurons

Subacuteandchronicneuronalinjury

• =degeneration• Neuronaldeathduetoprogressivedisease• Example:inAlzheimer• Celllossaffectingfunctionally relatedneurons(notnecessarilystructurallyrelated)

-Neuronaldeathusuallyisapoptoticdeathandisassociatedwithreactivegliosis.

GLIOSIS

• Gliosis isanonspecific reactivechangeofglialcellsinresponsetodamagetoCNS.Inmostcases,gliosis involvestheproliferation&/orhypertrophyofseveraldifferenttypesofglialcells,includingastrocytes,microglia,andoligodendrocytes.

• SO:GLIALCELLSCANPROLIFERATEANDDIVIDEINRESPONSETOINJURY.

Gliosissimplymeansincreasedglialcellsthinkofitascounterpartoffibrosisintherestofthebody

Reactionofastrocytestoinjury

• Astrocytesaretheprinciplecellsresponsibleforrepairandscarformation=gliosis• Reactiveastrocytesduringrepairundergochanges=gemistocyticastrocyte.

repair

• Astrocytesarethemaincellsresponsibleforrepairandscarformation(gliosis).• Injurycausesthefollowingchangesinastrocytes:• 1.hypertrophyandhyperplasiainastrocytes.• 2.enlargednuclei• 3.prominentnucleoli.• 4.increasedpinkcytoplasm.• 5.increased,ramifyingprocessesThesechangesinastrocytes:gemistocyticastrocyte.

gemistocytes

Gemistocytes

ReactionsofMicrogliatoInjury

• Microgliaaremesoderm-derivedphagocyticcellsthatserveastheresidentmacrophagesoftheCNS.• Theyrespondtoinjuryby(1)proliferating;(2)developingelongatednuclei(rodcells) (3)formingaggregatesaroundsmallfocioftissuenecrosis(microglialnodules);or(4)congregatingaroundcellbodiesofdyingneurons(neuronophagia).• Inadditiontoresidentmicroglia,blood-derivedmacrophagesmayalsobepresentininflammatoryfoci.

Microglialnodules..youcanthinkoftheseasgranulomas=aggregatesofmicrogliawhicharebasicallymacrophages.

Rodcells

ExamquestionAllofthefollowingstatementsarecorrectaboutthecellsseeninthispictureexcept:

A.originatefromastrocytes

B.indicatethestartofarepairprocessafterinjury

C.canbeseenaroundareasofdemyelination.

D.cellsoforiginarepermanentcells

E.canbeseeninthevicinityofresolvedinfarction.

Answertopreviousquestion

• D..becausegemistocytesoriginatefromastrocyteswhichareglialcellsandunlikeneurones,glialcellsdodivide;theyaren'tpermanent• therestofthechoicesareobviouslycorrect.Notethegemistocytescanbearesponsetoanyformofinjurysothechoicesaboutdemyelinationandoldinfarctarecorrect.

Examstylequestion

• A27yearoldfemaleunderwentacaesariansectionduringwhichshehadmassivebleeding.Hersystolicbloodpressuredroppedto45.Thebleedingcontinuedandshedied13hoursaftertheoperation.Ifyouweretodotheautopsyexamyouwouldexpecttoseewhichofthefollowingchangesinherneurons• A.cytoplasmicbasophilia• B.Prominentnucleoli• C.cellswelling• D.pyknosis• E.Gliosis

Explanationofthequestion

• Thescenariohereisaboutacuteischemicdamage.the13hourperiodmeanthatthemorphologicchangeshavedeveloped.Rememberthatredneuronesarethefirstmorphologicmanifestationofischemicdamageandtheyneed12hourstodevelop.• ObviouslytheonlycorrectchoiceisD,therestarewrongandglossiswrongbecauseit’snotaneuronaldamageandisnotanacutechange.

Afinalnote

• theexamquestionswillbesimilartothequestionsintheexamplesabove,andsomewillbeclinicallyoriented..soyouknowwhattoexpect.

• Foryourinformation:thewordneuroneiswrittenwithane attheend(British)orwithoutane (Americanstyle)

SUMMARY1/3• CNScellsareoftwotypes:neuronesthatarethefunctionalunitsandglialcellswhicharesupportive.glialcellsaremuchmoreabundant.• Glialarefourtypes:• 1.astrocytesthataresupportive,controlthemicroenvironment,formpartofthebloodbrainbarrierandareresponsibleforgloss(fibrosisandscarringofCNS).• 2.Oligodendrocytes:theircellmembranesformmyelinsheathimportantforinsulatingnerveimpulsesthusmakingtransmissionquicker• 3.Ependymalcells,linetheventriclesandspinalcordcavity.SpecialisedependymalformchoroidplexusthatsecretesCSF• 4.MicrogliaarespecialisedresidentmacrophagesimportantforinflammatoryandimmunologicreactionofCNS.

SUMMARY2/3

• Neuronesrespondtoacute injurybychangingtored neutrons.theyappear12hoursafterirreversibleinsultandcharacterisedbycytoplasmicshrinkageandincreasedeosinophilia(duetolossofNisslsubstance),pyknosis,lossofnucleolusandincreasedramifyingprocesses.• subacuteorchronicneuronalinjurycausesdegenerationanddeathofneurones,usuallybyapoptosis(todecreaseriskofdamaginginflammation).• chronicneuronalinjuryusuallyaffectsfunctionallyrelated neurones

SUMMARY3/3

• glialcellsarelessvulnerabletoacuteinjuryandrespondduringrepairprocessandgliosisformation.• Astrocytesarethemaincellsinvolvedinrepairandrespondbyforminggemistocytes:hypertophiccellswithlargeeosinophiliccytoplasm,largenucleiandprominentnucleoli• glialcellscanproliferatewhileneuronescannot(althoughneuronalprogenitorshavealimitedcapacitytodivide)• Microgliarespondtoinjuryby:hyperplasia,rodcells,neurophagiaandmicroglialnoduleformations.