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

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foundinthesepatients).Notsurprisingly,myastheniagravisissometimesseenalongwithother autoimmuneconditions(suchasthyroiditis,lupus,andrheumatoidarthritis).
(A)Transmissionacrossanormalneuromuscularjunction.(B)Transmissionisblockedbythepresence ofantibodiestothepostsynapticacetylcholinereceptors.
Box12.6Drug-InducedMyasthenia
Myastheniacanbecausedbyvariousdrugs,includingpenicillamine(usedtotreatWilson diseaseorrheumatoidarthritis),alphainterferons,andimmunecheckpointinhibitors (immunomodulatorydrugsusedtotreatseveraldifferentmalignancies).Thecheckpoint inhibitorsworkbypromotinganenhancedTcell–mediatedimmuneresponsetocancercells, butunfortunately,theycanalsocauseahostofsideeffectsduetoimmunesystem activation,includingmyasthenia,dermatomyositis,andpolymyositis.Unsurprisingly,theycan alsosignificantlyworsenpre-existingmyasthenia.SeeChapter16formoreonthe checkpointinhibitors.
Myastheniagravisisoftenassociatedwiththymicpathology,includingthymichyperplasiaor,inabout 10%ofpatients,thymoma.Thepreciseroleofthethymusinmyastheniagravisisnotunderstood;itmay containtheantigensthatinitiatetheautoimmuneprocessor,viaaTcell–mediatedmechanism,elicit autoantibodyproduction.Itisimportanttoappreciatethatnotallpatientswithmyastheniahavethymic abnormalities,andnotallpatientswiththymicabnormalitiesdevelopmyasthenia.Ofinterest,thymectomy improvesthediseaseinpatientsbothwithandwithoutathymomaand,whenfeasible,shouldbe performedassoonaspossiblebecause(1)thereisnocompellingreasontowaitifthepatientisagood surgicalcandidateand(2)itcanbecurative.
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Locationofathymoma.
Diagnosis.Suspectmyastheniagravisinpatientswhocomplainoffatigableweakness,particularlywhen accompaniedbyocularorbulbarfindings.Thediagnosisisconfirmedbyacombinationofclinical, serologic,and,ifneeded,electrophysiologicevaluations.
1. Neurologicexaminationandbedsidetests.Variousbedsidetestscanbeusedtoconfirmfatigableweakness.Lookfordifficultywith sustained upgaze andincreasingweaknesswith repeatedstrength testing. As mentionedearlier, checkingneck flexor weakness and askingthepatienttoperformasinglebreathtestarereliablesurrogatemeasuresofrespiratoryfunction.Thesensoryexaminationand deeptendonreflexesshouldbenormal.Therearetwootherold-schoolbedsidetestsforpatientswhopresentwithptosis:
a.
Theicepackte st. Applyanicepacktotheptoticeyelid forapproximately 2minutes.Improvementof2mmormorein the patient’sptosisisconsideredpositiveformyasthenia. Thistesthasa highdiagnosticsensitivity andspecificity fordistinguishing myasthenia-relatedptosisfromothercauses.Itisthoughtthatthecoolinginhibitstheactivityofacetylcholinesterase,theenzyme thatbreaksdownacetylcholine.
b. Thee drophoniumte st.Edrophoniumisafast-actingacetylcholinesteraseinhibitor.Yougiveitinsmall,incrementaldosesand
watch for improvement.Formanyyears thiswas thetest ofchoice,butthis drug isnolongeravailable for clinicaluse inthe UnitedStates.
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Apositiveicepacktest.
2. Laboratoryandserologictests.Levels ofcreatinekinase(CK)andinflammatorymarkersaretypicallynormal.DetectionofAChR antibodies or other antibodies associated with myasthenia gravis confirms the diagnosis. False positives are extremely rare. These serologicmarkersshouldbeusedfordiagnosticpurposesonly;theyarenotusefultotrackdiseaseactivity,assessseverity,ormeasure responsetotreatmentovertime.
3.  Electrophysiologic studies. EMG and NCS are most helpful in seronegative patients to confirm the diagnosis; they are often otherwiseunnecessary.Single-fiberEMGisthemostsensitiveelectrophysiologictest,butrepetitivenervestimulationislesstechnically demandingandisthereforeperformedmoreoften.Thedemonstrationofdecreasedmuscleactionpotentialamplitudewithslowratesof repetitivestimulation(i.e.,a“decrementalresponse”)issupportiveofthediagnosis.
4. Imaging.Allpatientsshouldhavemediastinalimaging(typicallywithaCTofthechest)toassesstheirthymicstatus.
EMGinapatientwithm yastheniagraviss hows decreas ingactionpotentialam plitudeswithrepeateds tim ulation.
Treatment.Acetylcholinesteraseinhibitors(AChEIs),usuallypyridostigmine,arefirst-linetherapy. Acetylcholinesteraseisanenzymethatrapidlybreaksdownacetylcholine.Blockingthisenzymetherefore increasestheconcentrationofacetylcholineinthesynapseandeffectivelyoverpowerstheimmunologic blockadeofthepostsynapticacetylcholinereceptor.Thesearesymptomaticmedications;theydonot modifythecourseofthediseaseoralterthelong-termprognosis.Commonsideeffectsarethosethat you’dexpectfromexcessparasympatheticactivity(themnemonicDUMBBELLScanhelpyouremember these,seeBox12.7).
Box12.7CholinergicEffects:DUMBBELLS
Diarrhea(andabdominalcramping)
Urination(frequencyandincontinence)
Miosis
Bradycardia
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Bronchospasm
Excitationofskeletalmuscles(fasciculations,twitching,paralysis)
Lacrimation
Lethargy
Salivation
Notethatallexceptthe“E”areduetomuscarinic(i.e.,affectingtheparasympatheticend­organs)effects.Thenicotiniceffects,duetoexcessacetylcholineattheneuromuscular junction,canbethemostdevastating.
Mostpatientswillrequireimmunosuppressivetherapyaswell.Corticosteroidsarefirstlinefor patientswhorequiremorethanAChEIsalone.Steroidshavearelativelyrapidonset,generallyover2to 3weeks,butcanactuallyworsensymptomsinitially.Commonlong-term“steroid-sparing”agentsinclude azathioprineandmycophenolate.Rituximab,amonoclonalantibodywhichtargetstheCD20antigenon mostBcells,isusuallyreservedforpatientswithsevereorrefractorydiseaseandismoreeffectivein patientswithMuSKmyasthenia.Eculizumab,amorerecentlyapprovedmedicationforrefractory myastheniathatactsbyinhibitingcomplementactivation,isanotheroption.Intravenousimmunoglobulin (IVIG)orplasmaexchange(PLEX)canalsobeusedchronicallyinpatientswhodonotrespondto,or cannottolerate,oralmedications.
Patientswiththymoma,whatevertheseverityoftheirdisease,shouldundergothymectomy. Thymectomyalsoappearstobenefitmostpatientswithoutathymomawhohavegeneralizeddisease, increasingthelikelihoodofremissionandleadingtoclinicalimprovementwhilereducingtheneedfor immunosuppressivetherapy.PatientswithMuSKmyasthenia,however,typicallydonotrespondto thymectomy.
Theprognosisisfavorable.Approximately10%ofpatientsdonotrespondtoorareunabletotolerate pharmacologictherapy.TheriskofrefractorydiseaseishighestinthosewithMuSKantibodies,an underlyingthymoma,youngerageatdiseaseonset,andfemalesex.
MyasthenicCrisis.Myastheniccrisisoccursinabout15%ofallpatientswithmyasthenia.Itisatrue neurologicemergencythatneedstobetreatedinanintensivecaresetting.Myastheniccrisisisdueto severeweaknessofthediaphragmandaccessorybreathingmuscles,resultinginacuterespiratoryfailure requiringventilatorysupport.Commontriggersincludesurgery,respiratoryorothersystemicinfections, andvariousmedications,mostnotablybetablockers,magnesium,andseveralantibiotics (aminoglycosidesandfluoroquinolonesaretwoofthemostcommonculprits).Treatmentconsistsof eitherIVIGorPLEX(thesetwomodalitiesarethoughttobeequallyeffective,althoughplasmapheresisis believedtohaveaslightlyquickeronsetofaction),aswellassteroids.
Myastheniccrisiscansometimesbeclinicallyconfusedwithcholinergiccrisis,whichcanhappen (althoughrarely!)whenpatientstakeanexcessoftheirAChEIs,resultinginoversaturationofthe acetylcholinereceptorstothepointthatthemusclesstopresponding.Althoughbothcanpresentwith severemuscleweakness,cholinergiccrisiswillalsobeassociatedwiththeDUMBBELLSsymptom constellation.
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Box12.8IVImmunoglobulinandPlasmapheresis
Aquickwordonthesetwotherapies.Theycomeupfrequentlyinneurology,andnotjustin themanagementofmyastheniagravis.
IVimmunoglobulin(IVIG)consistsofapooledmixtureofantibodiesderivedfromdonor plasma(asingledosecancontainplasmafromupto100,000donors!).Itisusedtotreat peoplewithimmunoglobulindeficiencies(whichmakessense)aswellasthosewith autoimmunediseases,suchasmyastheniaandGuillain-Barresyndrome(whichmakesless sense;therearemanytheorizedmechanismsbutnooneknowsforsurehowitworksin thesesettings).Majoradverseeffectsincludevolumeoverload(becarefulinpatientswith congestiveheartfailureorchronickidneydisease),hypercoagulability,andtransientaseptic meningitis.PatientswhoareIgAdeficientareatriskforanaphylacticreactionstoIVIG(as theymayhavepre-existingantibodiesagainstIgA),andthusyoumusteithercheckanIgA levelpriortotreatmentoruseanIgA-depletedformulation.
Plasmapheresis,alsoknownasplasmaexchange(PLEX),isanextracorporealtreatment, likehemodialysis,thatselectivelyremovesplasmaandreplacesitwithanotherfluid,usually donorplasma,colloid,orcrystalloid.Themechanismhereismorestraightforward:itworks byremovingthepathologicsubstance(inthecaseofmyastheniagravis,theAChR antibodies)fromcirculation.Sideeffectsincludehypotension,coagulopathy,and paresthesias.UnlikeIVIG,whichistypicallygiveneverydayfor3to5daysviaaperipheral IV,PLEXisgiveneveryotherday,typicallyforaboutaweek,andrequiresacentralline.
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Plasmapheresisexchangesdonorplasma,colloid,orcrystalloidforthepatient’splasma.
OtherDiseasesoftheNeuromuscularJunction
Thereareseveralotherdiseasesthatcancausetherapidonsetofpuremotorweaknessthatalsoaffectthe neuromuscularjunction.Thesearemuchlesscommonthanmyastheniagravis,buthereareafewyou shouldbeawareof:
Lambert-EatonSyndrome.Lambert-Eatoniscausedbyautoantibodiesdirectedagainstthepresynaptic calciumchannelsthatareresponsibleforthereleaseofacetylcholineintothesynapse.Abouthalfofcases ofLambert-Eatonsyndromeareparaneoplastic,mostoftenassociatedwithsmallcellcarcinomaofthe lung,andclinicalmanifestationstypicallyprecedethediagnosisofthecancer,oftenbyyears.Othercases appeartoarisespontaneously.
Likemyasthenia,patientspresentwithfluctuating,predominantlyproximalweakness.Unlike myasthenia,muscleweaknessimproveswithuse,cranialnerveinvolvementisuncommon,and hyporeflexiaispresent.Autonomicsymptoms,includingdrymouthandconstipation,arecommon.An EMGwillshowfacilitationwithrepeatedstimulationatfastrates,thusdistinguishingitfrommyasthenia; asinglestimulustoaperipheralnerveafter10secondsofisometricexercisecanleadtoanincrementof morethan100%intheamplitudeofthemotorresponse.AllpatientsdiagnosedwithLambert-Eaton syndromeshouldbeevaluatedformalignancyforupto5yearsaftertheinitialdiagnosis.
Thebesttherapyistotreattheunderlyingmalignancy.SymptomaticreliefcanbeobtainedwithIV
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immunoglobulinor3,4diaminopyridine,apotassiumchannelblocker.
(A)AnEMGtracingshowingincrementalincreaseinthesizeofactionpotentialswithrepeatedstimulation and(B)incrementafter10secondsofexercise.
Botulism.Thebotulinumneurotoxincausesparalysisbycompletelyblockingboththeneuromuscular junction(thenicotinicacetylcholinereceptors)andtheparasympatheticnervoussystem(themuscarinic acetylcholinereceptors).
LikeLambert-Eaton,theneurologicmanifestationsofbotulismaretheresultoftheblockadeof presynapticacetylcholinerelease.TheneurotoxinisproducedbythebacteriumClostridiumbotulinum andismostoftenacquiredthroughcontaminatedfood,particularlyasaresultofhomecanning,although woundinfectionsandinhalationofaerosolizedtoxin(hencetheputativeinterestofnefariouspartiesin usingthisasaweaponofbioterrorism)canberesponsible.Casesarerare,averaging100orsoperyear intheUnitedStates.However,becauseinfantsarepreferentiallyaffected(about70%ofallcases,most oftenfromcontaminatedhoney),thediseasecanbeparticularlydevastating.
Whenfoodpoisoningisthesource,gastrointestinalsymptomsusuallyoccurfirst,followedwithin12to 36hoursafteringestionbycranialnervepalsiesandadescendingflaccidparalysis,oftenwithdrymouth, nausea,andvomiting.Becausetheneurologicprocesscanprogresssorapidly,leadingtorespiratory failureanddeath,treatmentwithantitoxintherapyshouldbegivenbeforethediagnosisisconfirmedby EMG(whichwillshowanincrementalresponseofmuscleactionpotentialstorapid,repetitive stimulation)andisolationofthetoxinfromtheserumorstool.
Ifyoususpectbotulism,contactyourlocalhealthdepartmentrightawaytohelpwithtestingand treatment.Anycaseofbotulismisapublichealthemergencybecauseoftheriskoffurthercases originatingfromasinglecontaminatedsource.
Box12.9ThePositiveSideofBotulinumToxin
Botulinumtoxin,whichcanbesodevastating,hasalsobeenharnessedforgood. Formulationsoftheneurotoxinarenowusedinmultipleclinicalsettingswhererelaxationof themusculaturecanbebeneficial.Bestknownforitscosmeticuses(reducing“frownlines” andthelike),itisalsousedtotreatchronicmigraine,blepharospasm,cervicaldystonia,and more.Thebeneficialeffectisonlytemporary,andthustreatmentsmustberepeatedevery fewmonths.
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Injectionofbotulinumtoxintoreducechronicmigraine.
OrganophosphatePoisoning.Theorganophosphateinsecticidesarelong-actingacetylcholinesterase inhibitorsthatcauseexcessacetylcholinetoaccumulateatmuscarinicsynapsesandneuromuscular junctions.
Theclinicalpictureisoneofparasympatheticoverdrive:theDUMBBELLSconstellationofsymptoms can,ifsevere,progresstoconfusion,seizures,andcoma.Althoughthepathologyhereisessentiallythe oppositeofthatseeninmyasthenia—toomuchversustoolittlestimulationoftheacetylcholinereceptors —theycanlookidentical,sinceanexcessofacetylcholinecaneffectivelysaturatethereceptors,resulting infasciculations,weakness,and,ultimately,paralysis.
Treatmentiswithatropine(anantimuscarinicagentthatwillreversethemuscarinicbutnotthe nicotiniceffects)andpralidoxime(whichcanregenerateacetylcholinesteraseifgivenearlyafter exposure).
Myopathies
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Sohereweare—we’vetraveledasfaraswecandownthemotorpathways,acrosstheneuromuscular junction,toarriveatthemusclesthemselves.Beforewegetintothespecificprimarymuscledisorders thatyoushouldknow,let’saskafundamentalquestion—howdoweknowifadiseaseisprimarily
neurologicormuscular?
DistinguishingNeurologicFromMuscularDisease.Theanswerisnotalwayssimple,andyoumay needtoresorttoelectrodiagnostictestingandmusclebiopsytopindownthediagnosis.Butinmany situationsthehistoryandexaminationwillserveasreliableguides.Somekeypoints:
Iftherearesensoryabnormalitiesordepressed(orincreased)reflexesearlyinthediseaseprocess, youare almostcertainlydealing with a neurologicdisorder.Themanifestations ofmyopathies are purelymotor. Myopathiesareusuallysymmetricandtendtobeproximal;neuropathiescanbeasymmetricandare oftendistal. Inthecaseofinflammatorymyopathies,theremaybe(butnotalways)tendernessovertheinvolved muscles. ALS(see page275)andGuillain-Barresyndrome (seepage284),becausetheyarepredominantly motor in presentation, can mimic primary myopathies. But their distinctive histories and clinical presentationswillusuallyleadyouintherightdirection. What about neuromuscular disease versus myopathy? The distinction between neuromuscular diseases,suchasmyastheniagravis,andthemyopathiesthatwearegoingtodiscussnextisusually notdifficultiffornootherreasonthanthatmyastheniahasanumberofuniquefeatures,allspelled outabove.Butwhenthepresentationisnotclassic,thedistinctioncanbechallenging.Relyonyour neurologictoolbox—yourexamination,aswellaslaboratoryandelectrodiagnostictesting—andyou willarriveattheanswer.
Wecangroupthemyopathiesintotwomajorcategoriesthatshouldhelpyoukeepthingsstraight: inflammatoryandnoninflammatorymyopathies.
TheInflammatoryMyopathies
Theseincludedermatomyositis,inclusionbodymyositis,andimmune-mediatednecrotizingmyopathy. Wewillincludepolymyositishereaswell,butasperourearlierdiscussion(seeBox12.1onpage307), pleasekeepinmindthatpolymyositisisactuallyamuchlesscommonsyndromethanpreviouslybelieved. Patientswithaninflammatorymyopathycomplainchieflyofweaknessandmildmyalgias.
PolymyositisandDermatomyositis.Polymyositisisanautoimmunediseasethataffectstheskeletal muscles.Iftheskinisalsoaffected(seeimagesbelow),wecallthediseasedermatomyositis.
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Examplesof(A)theclassicfacialheliotroperashofdermatomyositis,and(B)Gottronpapulesthatcan occurovertheextensorsurfacesofthehands.(A,reprintedfromCouncilML,SheinbeinD,CorneliuLA. TheWashingtonManualofDermatologyDiagnostics.WoltersKluwer;2016;andB,reprintedfrom GoodheartHP.Goodheart’sSame-SiteDifferentialDiagnosis:ARapidMethodofDiagnosingandTreating CommonSkinDisorders.WoltersKluwer;2010.)
ClinicalManifestations.Patientspresentwithprogressive,symmetric,andpredominantlyproximal muscleweakness.Theywilloftenreportdifficultyclimbingstairsorgettingupfromachair.Patientsmay alsoexperienceflu-likesymptoms(low-gradefevers,malaise,andfatigue).Abouthalfofpatientshave muscletenderness.Interstitiallungdiseaseandcardiacmyositiscandevelop.Nearlyhalfofpatientswith dermatomyositis(farfewerwithpolymyositis)haveanunderlyingmalignancythatisusuallyapparent within2yearsofthediagnosisofthemyopathy.Womenareaffectednearlytwiceasoftenasmen.
LaboratoryStudies.Muscleenzymes(creatinekinase,transaminases,andaldolase)andnonspecific inflammatorymarkers(erythrocytesedimentationrate[ESR]andC-reactiveprotein[CRP])willbe elevated.Testingshouldalsobeperformedforantinuclearantibodies(ANA),whichcanbedetectedin about60%ofpatients,aswellasmyositis-specificantibodies,suchasanti-Mi2,anti-MDA5,andanti­TIF1y.
BiopsyandEMG.Thediagnosiscanbeconfirmedbymusclebiopsy,whichwillalsohelpdistinguish polymyositisfromdermatomyositis:theformerwillshowendomysialinflammation,thelatterperimysial inflammation(thinkdermatomyositis=inflammationthat’sclosertotheskin;seethepicturebelow).
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