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Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_186_библиотеки_им_акад_М_И_Перельмана

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Oligoclonalbandsonelectrophoresis.Thefirstshowsanormalelectrophoresis.Thesecondisfroma patientwithMS.
IfYouAreStillNotSureWhatIsGoingon.Althoughrarelyusedanymore,visualandsomatosensory evokedpotentialsmeasurethespeedofnerveconduction,andtheywillprovetobeabnormalinsome
patientswithMS.Theiraccuracyisn’tgreat,butintherightclinicalcontextanabnormalevokedpotential may,indifficultcases,reveallocaldysfunctioninaCNSregionsuchastheopticnerveandthusbethe finalpieceofevidencethatmakesyoureasonablyconfidentthatyourpatienthasMS.
DifferentialDiagnosis
ThedifferentialdiagnosisofMSisextensivegiventhemanifoldwaysinwhichitcanpresent.Amongthe mostimportantconfoundersare:
OtherinflammatorydiseasesthataffecttheCNS(includingNMOSD,ADEM,Neurosarcoidosisand SusacSyndrome;seediscussionbelow,pages243-244) Vasculardiseases—CNSvasculitiscancausea scatteringofneurologicdeficitsoften duetosmall bleedsorstrokesthatmaymimicsomeofthefeaturesofMS(seepage88) Infections—Lymedisease shouldbe considered (althoughfulminant neuroborreliosis is rare), HIV andsyphilis Metabolicdiseases—ThinkvitaminB12,copper,andzincdeficiencies CNS malignancies—Among these, you need to consider lymphoma, primary neoplasms, and paraneoplasticsyndromes(seeChapter16) Psychiatricdisorders—Considerdepressionoranxietywithsomaticfeatures(e.g.,tingling,fatigue, andbrainfog);thesecanmimicsymptomsofMSbutwillnotbeassociatedwithobjectivefindings
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onneurologicexamination,andimagingwillbenormal
SeveralprimaryinflammatoryconditionscanaffecttheCNSandcloselymimicthewayMSpresents andevolves.AlthoughlesscommonthanMS,theseareimportantforyoutoknow.
Neuromyelitisopticaspectrumdisorder(NMOSD)comprisesseveralrelatedbutdistinctentities thatpresentmostcommonlywithopticneuritisortransversemyelitis(seepage267)andlessoften withhiccupsor intractableemesis(the resultofinvolvement ofthe areapostrema inthemedulla). Nearlyall cases are associatedwith the aquaporin-4 (AQP4)-IgGautoantibody(aquaporinis a water channel protein presentthroughout the body, including the CNS); a smaller percentage are seropositiveformyelinoligodendrocyteglycoprotein(MOG).
1
NMOSDcancausesevereattacksandprofounddisability.NMO-relatedopticneuritis,forinstance, istypicallymuchmoreseverethanMS-relatedopticneuritis,withamorerapidcourseandamore devastatingoutcomeifleftuntreated. TodiagnoseNMOSD:
Suspect the disease because of the clinical picture as well as the appearance of the lesions on MRI. A brain MRI isoften unremarkable,butthespinalcordmayreveal thick, longlesionsspanningmultiple vertebrallevels (unlike the “short-segment” lesionscharacteristicofMS). Testthe blood forAQP4autoantibodies(moresensitivethantestingthe CSF)and,ifnegative,forMOGantibodies. Unlikein MS,theCSFoftenshowsanelevatedwhitecellcountandoligoclonalbandsareusuallyabsent.Accuratediagnosisisimportant, because,comparedwithMS,NMOSDoftenrequiressignificantlylongercoursesofcorticosteroidtherapy(oftenwithadditional plasmapheresis,commonlyreferredtoasPLEX)topreventrelapsesanddoesnotrespondtothedisease-modifyingmedications thatare used for MS. Rituximab and eculizumab, among others, are used instead, although evidence of their efficacy in this settingisstillrelativelysparse.
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NMOlesioninthecervicalspinalcord(arrow).ContrastthiswiththesmallerMSspinalcordlesionpictured infigureBonpage241.(ReprintedfromSanelliP,SchaeferP,LaurieLoevnerL.Neuroimaging:The Essentials.WoltersKluwer;2015.)
Acute disseminated encephalomyelitis (ADEM)is an acute, rapidly progressive, and typically monophasicdiseasecausedbyautoimmunedemyelination.Itismostoftenseeninchildrenfollowing a bacterial or viral infection. The presentation is variable but typically includes both new, focal neurologicdeficitsandsystemicsymptomssuchasfever,headache,andnausea.Unliketherelatively well-circumscribedovoidlesionsonMRIcharacteristicofMS,thelesionsassociatedwithADEM are bigger and more diffuse (often described as “fluffy”) and, importantly, tend to enhance with contrast all at once. The CSF will show a lymphocytic pleocytosis (although typically less than 100cells)and, likeNMOSD,willnotdemonstrateoligoclonalbands.Treatmentis withhigh-dose corticosteroids,followedbyplasmaexchangeifneeded.
The“fluffy”lesionscharacteristicofADEM.(ReprintedfromBrantWE,HelmsCA.BrantandHelms Solution.WoltersKluwer;2006.)
Theseareahostofstillotherimmunologic/inflammatory disordersthatcanmimicMSbut thatare evenrarerthanNMOSDandADEM.Twoyoushouldbeawareofare:
Neurosarcoidosis,the neurologic manifestationofsarcoidosis. Like MS, itcanaffect the brain,optic nerve, andspinal cord. Unlike MS, neurosarcoidosis can affect just about everything else in the nervous system, includingthe peripheralnerves and meninges.  Susac syndromeis an even less common disorder. It is an inflammatory vascular disease that most often presents with sensorineural hearingloss,encephalopathy,andretinal arteryocclusions. Susac canlookverysimilar toMSonMRIbut has a particularpredilectionforthecorpuscallosum.
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ClinicalCourse
ThemostcommoncourseforMSisoneofrelapseandremission.Withtreatment,mostpatientswilldo verywellformanyyears.Asignificantminorityofpatients,evenwithouttherapy,willonlyhaveoneor severalattacksandwillsufferverylittledisability.However,withouttreatment,abouthalfofpatients willevolveintosecondaryprogressiveMS.
Arelapseorexacerbationisdefinedasanepisodeofnewneurologicdeficitordisabilitythat developsoverseveralhours,persistsformorethan24hours,andoccursintheabsenceoffeveror infection.Recoveryoccursslowlyoverweekstomonthsbutmaynotbetotal,andmanypatientswillhave somedegreeofresidualneurologicdeficit.Thefrequencyandseverityofrelapsesisunpredictableand variesgreatly.Fortunately,treatmentcangreatlyimprovetheoverallprognosis.
Box9.6Pseudorelapse
Arelapsemustbedistinguishedfroma“pseudorelapse,”aworseningofneurologic symptomsfromalreadyexistingdeficits.Manypatientswillexperienceapseudorelapsewith anincreaseinbodytemperaturecausedbyexercise,hotweather,infection,orfever.This typeofpseudorelapseiscalledtheUhthoffphenomenon.Itdoesnotsignifyanewattackor lesion,justafurtherdecreaseinelectricalconductivitycausedbytheincreasedtemperature. Theseeventsaretypicallytransient,andpatientswillreturntotheirbaselineoncetheycool down.Stressandinfectionareothercommontriggersthatcancausepseudorelapses.
PatientswithprimaryprogressiveMShaveasteadierdecline.Thisdiagnosisismadebydocumenting progressiveneurologicdisabilitywithoutrelapsesoveraperiodofatleast1year.
Treatment
ThetreatmentofMSis3-fold:treattheacuteattacks,reducetheriskoffutureattacksanddisability,and managesymptoms.Keypoint:Patientswithclinicallyisolatedsyndrome(CIS)whoareathighriskof progressiontofull-blownMSshouldalsobeoffereddisease-modifyingtherapy(seeprognosticfactors below).
TreatingAcuteExacerbations.High-dosecorticosteroidsremainthemainstayoftreatmentforanacute relapse.Steroidsacceleraterecoverybutdonothaveanydefinitiveimpactonapatient’slong-term prognosisorriskoffutureattacks.Oralandparenteralformulationsareequallyeffectiveandsafe,but patientswithsevereexacerbationscausingacutedisabilityaregenerallyhospitalizedforintravenous(IV) steroidsandclosemonitoring.Asalways,whendealingwithhigh-dosesteroids,bloodglucoselevels mustbecarefullytrackedandaproton-pumpinhibitorprophylacticallyprescribedforgastricprotection. Insomnia,agitation,andpsychosisareotherimportantsideeffectsofhigh-dosesteroids.Foran exacerbationthatdoesnotrespondtosteroids,plasmapheresisisthesecond-lineoption.
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IVsteroidsaregenerallygiveninahospitalsetting.
ModifyingtheDiseaseCourse.Yourmantra:treatearly.Diseasemodifyingtherapyreducestheriskof recurrentattacks,theappearanceofnewlesionsonMRI,anddisability.Diseasemodifyingdrugsalso reducetheriskthatpatientswithCISwillprogresstoMS.Diseasemodifyingdrugsshouldnotbeusedto treatacuteexacerbationsanddonotreduceexistingsymptomatology.
Severalclassesofdrugsarenowavailabletotreatrelapsingremittingdisease:
Injectableagents: Interferonbeta was thefirsteffective diseasemodifyingdrug. Theinterferons are still sometimes usedbecauseoftheir provensafetyrecord, buttheyare less effectivethanthe neweroraldrugs. Glatiramer acetate is anotherinjectable drug that’salso beenaround for many yearsandcanworkwellwithfewserioussideeffects. Oralagents:Manypatientspreferoralagentstoinjectableones,andtherearenowseveralonthe market.Dependingontheparticularagent,patientsneedtohavetheircompletebloodcountandliver functiontestsmonitoredperiodically.Fingolimod,dimethylfumarate,andteriflunomide arethree ofthemorecommonlyprescribed. Monoclonalantibodies:TheseagentsaregivenviaIVinfusion.Theyarehighlyeffectivebutcarry more risk. Natalizumab (directed against alpha4-integrin, Natalizumab binds and prevents lymphocyte adherence to vessel walls, thereby reducing lymphocyte entry into the CNS) and ocrelizumab (directed against the B cell surface antigen CD20) are the two most commonly prescribed. Natalizumab in particular requires regular monitoring of JC virus antibody status, becausepatientswhohavebeenexposedtoJCvirus(approximatelyhalfofthegeneralpopulation) areatsignificantlyhigherriskofdevelopingprogressivemultifocalleukoencephalopathy(PML,see page218)andmustbeswitchedtoanothermedication.
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Ingeneral,themoreeffectivethedrug,thegreatertheriskofpotentiallyserioussideeffects.However, thesemedicationsarewelltoleratedbythevastmajorityofpatients.
Untilrecentlywehadnodisease-modifyingagentsforprimaryprogressiveMS.However,ocrelizumab hasbeenfoundtoreducethepercentageofpatientswhoexperiencedisabilityanddiseaseprogression. Themostcommonsideeffectisinfection,particularlyupperrespiratoryinfections.PMLcanalsooccur. Anotherdrug,siponimod,appearstobeeffectiveinlimitingdisabilityinsecondaryprogressiveMS.
SymptomaticTreatment.Patientswhodeveloplong-termcomplicationsofMSoftenrequireadditional helptomanagetheirsymptomaticburden.Thereisalonglistoflifestyleinterventionsandmedications thatcanbehelpful.Anticholinergicdrugs(forexample,oxybutynin)areoftenprescribedforurinary incontinence;baclofenisoneofthemostcommonmedicationsprescribedforspasticity;gabapentinis usedtotreatneuropathicpain.
Whataboutcannabinoids?Thedataherearefarfromideal,butevidenceisslowlymountingthat cannabinoidscanbeatleastmodestlyeffectiveforreducingspasticityandneuropathicpaininMS(asof thiswriting,cannabinoidsarenotUSFoodandDrugAdministrationapprovedforthisindicationinthe UnitedStates).
Box9.7VitaminDForMS?
Variousvitaminsanddietaryinterventionshavebeenstudied,andnoconsistentbenefithas beenfound,withonepossibleexception.TheassociationoflowlevelsofvitaminDwithan increasedriskofMSinCaucasianpopulationswouldsuggestthatsupplementationmightbe useful.Althoughthebenefitshaven’tbeenasprofoundasinvestigatorshadhoped,inatleast somepatientsvitaminDsupplementationdoesappeartoreducetheappearanceofnew lesionsonMRIaswellastherateofrelapseandprogressiontodisability.Mostpatientsare thereforeplacedonvitaminDtherapy,aimingforlevelswithinthenormalrange.
Prognosis
MSisatreatabledisease.Thegoalforallpatientsiswhatneurologiststerm“noevidenceofdisease activity”(NEDA)inthefirstyearafterdiagnosis.NEDAmeansnoclinicalrelapses,nonewlesionson
MRI,andnoaccumulationofdisability.Astheyearsgoby,however,thisgoalbecomesmoreandmore difficulttomaintain.
Itisvirtuallyimpossibletopredictthecourseofthediseaseinanygivenpatient;however,favorable prognosticfeaturesinclude:
femalesex, youngerageatdiagnosis,and littledisabilityat5yearsafterdiagnosis
Opticneuritisasthefirstsymptomportendsamorefavorableprognosisintheshortterm,butlong-term disabilityisnobetterorworsethaninpatientswithotherpresentations.
Poorerprognosticfeaturesinclude:
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malesex, olderageatdiagnosis, frequentattacksearlyinthecourse, progressivediseasefromthestart,and cerebellarsymptomsasthefirstclinicalevidenceofthedisease.
Initiatingtherapywiththemoreaggressivemedicationsisoftenrecommendedforpatientswithpoor prognosticfeaturesormultipleMRIlesionsbecausetheyareatgreatestriskofaccumulatingdisability.
MSandPregnancy
WomenwithMScanhavenormalpregnanciesandbreastfeedsafely.
PregnancyappearstodecreasethefrequencyofMSexacerbations,butanincreaseinthenumberof exacerbationsinthepostpartumperiodessentiallybalancesouttheequation.Pregnancydoesnotchange thelong-termprognosisofthedisease.WomenwithMShaveaslightlyincreasedrateofcaesarian deliveriesandlowbirthweightbabies,buttheredoesnotappeartobeanincreaseinstillbirths,ectopic pregnancies,birthdefects,orspontaneousabortions.Whenpossible,womenshouldnotbeondisease­modifyingdrugsduringpregnancy,butthisrecommendationhasnotbeenadequatelystudied. Exacerbationsaretreatedwithcorticosteroids.
Thetake-awayisthatpregnancyisnotcontraindicatedbyMS,butrisksandbenefitsshouldbeweighed inpatientswithseverediseaseinwhomtemporarilystoppingorsignificantlyalteringtreatmentposes highrisk.
Breastfeedingissafewithsomediseasemodifyingdrugs,butthedataarelimitedforthenewerdrugs, soconsultwithanMSspecialistandobstetriciantoguidemanagement.MSitselfisnotacontraindication tobreastfeeding.
AutoimmuneEncephalitis:OneOtherImmunologicCNS DiseaseYouShouldKnow
Foralongtime,wethoughtofencephalitisasprincipallyaninfectiousdisease,mostcommonlycausedby herpessimplexvirusormosquito-ortick-bornepathogens(seepage215).Butencephalitiscanalsobe causedbythebody’sownimmunesystemattackingthebrain.Asitturnsout,autoimmuneencephalitisis nearlyascommonasitsinfectiouscounterpart.Considerationofthisdiagnosisiscrucial,asrapid treatmentresultsinsignificantlybetteroutcomes.
Therearetwomaintypesofencephalitisthatareconsideredtobeimmunemediated:
Paraneoplastic encephalitis, which is invariably malignancy related (although it often presents prior to the patienthaving any awareness of anunderlying malignancy), caused notbythe cancer itselfbutbytheimmunologicreaction(i.e.,antibodies)thatthecancerprovokes.  Autoimmune encephalitis, which is most often due to autoantibodies directed against neuronal surfaceantigens.
Thenomenclatureisalittlemisleading,asparaneoplasticencephalitisisbydefinitionautoimmune,and autoimmuneencephalitiscanbeparaneoplastic.Don’tworrytoomuchabouttheclassification.Here’s
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whatyoushouldknow:
Presentation
Ingeneral,immune-mediatedencephalitispresentssubacutely,overweekstomonths,althoughitcan sometimesevolvemuchmorerapidly.Therearethreemainanatomicaltargets.
Limbicencephalitis,asthename implies,involvesthestructuresofthelimbicsystem,including the amygdala, hippocampus, hypothalamus, and limbic cortex2 . It is considered a classic paraneoplastic syndrome but can occur without an underlying malignancy. Common symptoms includememoryloss,cognitiveandbehavioralchanges(thesepatientsareofteninitiallyadmittedto psychiatricwardsowingtoagitation,disinhibition, andvariousbizarrebehaviors), focal seizures, and symptoms related to hypothalamic dysfunction such as hyperthermia and endocrine abnormalities. MRI can be normal, but often shows increased fluid-attenuatedinversion recovery (FLAIR)signalinthemesialtemporallobes. One form oflimbicencephalitis, calledanti-NMDA receptor encephalitis, is most often seenin youngwomenandiscausedbyautoantibodiesdirectedagainsttheglutamatergicNMDA(N-methyl­D-aspartate)receptor. Orofacial dyskinesias(whichlook likechoreoathetoidchewing movements, see page 346), as well as severe autonomic instability, are common. Anti-NMDA antibodies are mostfrequentlyassociatedwithovarianteratomas.Asecondformoflimbicencephalitis,anti-LGII encephalitis, is more likelyto be seenin older patients andin men. It presents more often with faciobrachial dystonic seizures, peripheral neuropathy, and hyponatremia. LGII antibodies are typicallynotassociatedwithanunderlyingneoplasm.
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CoronalMRIdemonstratesprominentFLAIRhyperintensitiesinthebilateralmesialtemporallobes(solid arrow)andcingulategyrus(dashedarrow),characteristicoflimbicencephalitis.(ReprintedfromScheld WM,WhitleyRJ,MarraCM.InfectionsoftheCentralNervousSystem.4thed.WoltersKluwer;2014.)
Brainstem encephalitiscan present with a wide range of symptoms localized to the pons and medulla, including extraocular movement abnormalities, dysphagia, dysarthria, and vertigo. This disorderoftenoccursinconjunctionwithparaneoplasticcerebellardegeneration. Encephalomyelitispresentswith diffuse involvement ofthenervoussystemincludingtheregions listedabove,the spinalcord, andthe dorsal rootganglia. Mostcases are associated with anti-Hu antibodies(whicharealsofrequentlyassociatedwithlimbicencephalitis,sensoryneuronopathy,and cerebellardegeneration).Smallcelllungcanceristhemostcommonlyassociatedmalignancy. Other,lesscommontargetsincludetheopticnerves,retina,andthedorsalrootganglia.
Diagnosis
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