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Ростовский Государственный Медицинский Университет

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SecondaryParkinsonism

Thereareanumberofotherdiseaseprocesses,medicationsandtoxinsthatcancauseparkinsonian symptoms;whenthisoccurs,itisreferredtoassecondaryparkinsonism,i.e.,parkinsonismcausedby somethingotherthanprimaryoratypicalPD.

 Vascular disease. Multiple small strokes involving the basal ganglia can cause parkinsonian symptoms,typicallyaffectingthelowerbody andsparingthefaceandupperbody.Tremoris often absent.  Normal pressure hydrocephalus can present with a shuffling gait that can be clinically indistinguishablefromthatofPD.Seepage199. Antidopaminergicmedications.Antipsychoticmedications(typicalantipsychoticslikehaloperidol and atypical antipsychotics like risperidone) and antiemetics (metoclopramide and prochlorperazine) can cause features of parkinsonism even months to years after starting the medications. Postencephaliticparkinsonismcandevelopafterviralinfectionsofthebrainparenchyma. Toxins, such as carbonmonoxide, MPTP(ananalogue ofthe opioid meperidine) andmanganese, canproduceparkinsoniansymptoms. Posttraumatic parkinsonism,aresultof repeatedheadtrauma, has beengettinga lot ofattention lately,butaswementionedearlierinChapter4,thecausativerelationshipisstillbeinginvestigated. Wilsondiseaseisonesecondarycauseofparkinsonismyouneverwanttomiss.Ittypicallypresents inpatientsbeforetheageof40yearsandiscausedbyanautosomalrecessivegeneticmutationthat leadstocopperoverload(themutationinvolvestheATPB7geneonchromosome13thatencodesa copper-transportingATPase).Neurologicsymptomsincludevariousmovementdisorders(including parkinsonism with a resting and/or action tremor,ataxia and chorea) and cognitive decline.Liver diseaseisoften thefirstsign,butneurologicfeaturescanprecede evidenceofhepaticdysfunction. Thediagnosismustbesuspectedoryouwillmissit;youngpatientswhopresentwithanyfeaturesof parkinsonism should always be tested with a serum ceruloplasmin and a 24-hour urine copper measurement.AnophthalmologistmayfindKayser-Fleisherringsonslit-lampexamination.

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Kayser-Fleisherrings(thedarkringaroundtheiris)areduetocopperdepositioninDescemet membrane,betweenthestromaandendotheliallayerofthecornea.(ReprintedfromRapuanoC.Cornea. 3rded.WoltersKluwer;2018.)

Box13.9CarbonMonoxidePoisoning

Carbonmonoxide(CO)isacolorless,odorlessgasthatisproducedanytimeafossilfuelis burned.Fires,heaters,andcarexhaustarecommonsources.AcutesymptomsofCO poisoningincludeheadache,confusion,andtheclassic“cherryred”face,whichiscausedby elevatedlevelsofcarboxyhemoglobinintheblood.Parkinsonismcandevelopdaystoweeks afteracutepoisoning.Classicimagingfindingsincludehypodenselesionsinthebilateral globuspallidusonCTandhyperintenselesionsinthebilateralglobuspallidusonMRI(see imagebelow).Noparkinsoniandrugshaveproveneffective,butsymptomscan spontaneouslyimproveovertime.

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SeveralmonthsafteranepisodeofacuteCOpoisoning,hyperintenselesionscanbeseeninthe bilateralglobuspallidusonT2-weightedMRI.ModifiedfromGriggsRC,JoyntRJ.BakerandJoynt’s ClinicalNeurologyonCD-ROM.WoltersKluwer;2004.

OtherMovementDisorders

PDisnottheonlyneurologicdiseasethatprimarilyaffectsmovement.Itisbyfarthemostcommon

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hypokineticdisorder,thatis,onethatprimarilyreducesmovement,acategorythatalsoincludesthe atypicalparkinsoniansyndromesandsecondaryparkinsonism.Tremoristhemostcommonhyperkinetic disorder,thatis,onethatresultsinexcessiveinvoluntarymovements.However,therearenumerousother abnormalmovementsandmovementdisordersinthehyperkineticcategorythatareimportanttodiscuss. Amongthemare:

ChoreiformdisordersandHuntingtondisease Tardivedyskinesiaandotherdrug-inducedmovementdisorders Dystonia Myoclonus Ticdisorders Sleep-relatedmovementdisorders

ChoreiformDisordersandHuntingtonDisease

Chorea,fromtheGreekwordfordance,describesadyskinesia(definedasanyabnormal,involuntary movement)characterizedbyirregular,relativelyrapidmovementsthatcanappeartoflowsmoothlyfrom onepartofthebodytoanother,producingadance-likeillusion.

Thedance-likemovementsofchorea.

Choreawasfirstdescribedasaconsequenceofbeta-hemolyticstreptococcalinfection,centuries beforetherewereantibioticstotreattheinfection.TermedSydenhamchoreaafterThomasSydenham

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whofirstreportedit,itwasalsoreferredtoasSt.Vitusdance(St.Vitusisthepatronsaintof,among others,dancers).Syndenhamchoreaoccursmonthsaftertheinfection,isprobablyautoimmuneinorigin, andisoftenprecededbycardiac(rheumaticheartdisease)andrheumatologicmanifestations.Sydenham choreaisusuallyself-limited.Itisextremelyraretoday.

Choreacanbeacquiredorinherited.

Acquiredchoreiformdisordersincludechoreaassociatedwithendocrineabnormalities(suchas acutehyperglycemiaandthyrotoxicosis),infections(HIVandherpesencephalitis),andautoimmune

diseases(systemiclupuserythematosusandantiphospholipidsyndrome).

Choreagravidarumisthetermusedtorefertopregnancy-inducedchorea.Ittendstodevelopafterthe

firsttrimesterandimprovelaterinthethirdtrimesterorafterdeliveryandismorecommoninwomen withahistoryofsystemiclupuserythematosus,antiphospholipidsyndrome,andotherpredisposing conditions.

Choreacanoccurasaparaneoplasticphenomenon.Itcanalsobecausedbymedicationsanddrugsof abusethatsharethefeatureofcausingahyperdopaminergicstate(PD,whichisahypokineticdisorder,is causedbythelossofdopaminergicneurons,soitisnotsurprisingthatchorearepresentstheotherendof thedopaminespectrum).Amongthesesubstancesarelevodopa,anticonvulsants,lithium,anticholinergic drugs,amphetamines,andcocaine.

Oftheinheritedchoreiformdisorders,Huntingtondiseaseisthemostcommon.Thisprogressive neurodegenerativediseaseis,initsmostprevalentform,inheritedasanautosomaldominanttrait.Itisthe resultofatrinucleotideCAGrepeatonchromosome4inwhatisaptlytermedthehuntingtin(notethe spelling)gene,whichisinvolvedinmultipleintracellularprocessesincludingpostsynaptictransmission. ExpansionofthenumberofCAGrepeatsoccurswitheachsuccessivegeneration;thisphenomenonis knownasanticipationandresultsinanincreasinglysevereandearlier-onsetphenotype.Thekey pathologicfindingisthelossofneuronsinthecaudateandputamen(thecaudateandputamentogetherare knownasthestriatum;thisprocessisthereforetermedstriatalatrophy).Imagingcanshow hydrocephalusexvacuo(i.e.,expansionoftheCSFspacesduetogeneralizedvolumeloss)andcaudate atrophy.

(A)Significantcaudateatrophy(seearrows)resultsinenlargedlateralventricles.(B)Enlargedlateral ventriclesandcorticalatrophyseenonanMRIofapatientwithHuntingtondisease.(ModifiedfromRubin E,ReisnerHM.PrinciplesofRubin’sPathology.WoltersKluwer;2018.)

PatientswithHuntingtondiseasetypicallypresentwithchoreabuteventuallydevelopaggressive behavior,severedepression,anddementia,aswellasprofoundweightloss.Symptomsusuallybeginin

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earlyadulthood.Itisuniversallyfatal.Thediagnosisismadebyrecognizingtheseclinicalfeaturesina patientwithafamilyhistoryofthediseaseandcanbeconfirmedwithgenetictesting.

Treatmentissupportive.Avarietyofmedicationscanbeusedtosuppressthemovementdisorder, amongthemneuroleptics(e.g.,haloperidol),benzodiazepines(e.g.,clonazepam),andagentsthatdeplete dopamine(suchasreserpineandtetrabenazine;thelatterisspecificallyrecommendedbytheAmerican AcademyofNeurology).Deepbrainstimulationisalsobeingstudiedasatherapeuticoption.

Box13.10AthetosisandHemiballism

Thesearetwootherhyperkineticmovementdisordersyoushouldknowaboutthatarepart ofthechoreiformspectrum.Comparedwithchorea,athetosisischaracterizedbyslower, morewrithingmovements;whenthetwocoexist,themovementsaretermed “choreoathetoid.”Hemiballismischaracterizedbysuddenlarge-amplitudeflingingmovements ofanextremityandclassicallylocalizestolesionswithinthesubthalamicnucleus.

Benignhereditarychoreaisanotherformofinheritedchorea.Itpresentsininfantsoryoungchildren withhypotonia,generalizedchorea,andgaitdysfunction.Itisinheritedasanautosomaldominant disordermostoftenassociatedwithathyroidtranscriptionfactorgenemutation.Symptomstendnotto progressandmaylessenovertime,althoughcompleteremissionisuncommon.Itisnotalways“benign,” however,andcanbeassociatedwithlearningdisabilities,attentiondeficitdisorder,andamultitudeof issuesaffectingotherorgansystems(including,notsurprisingly,thyroiddisease).

TardiveDyskinesia

Tardivedyskinesiaisacomplicationoflong-termuse(thinktardy,ordelayed)ofdopaminereceptor– blockingmedications,suchasantiemeticsandantipsychotics.Theriskwiththesecond-generation antipsychotics(suchasrisperidone,olanzapine,andaripiprazole)isthoughttobelessthanwiththefirstgenerationantipsychotics(e.g.,chlorpromazineandhaloperidol),butthisnotionhasbeenquestioned.The second-generationantipsychoticsareincreasinglybeingusedtotreatdepression—approximatelyonein fivenursinghomeresidentsisononeofthesemedications—sotheriskoftardivedyskinesiaisareal concern.

Patientswithtardivedyskinesiaexperiencedisablingchoreicandchoreoathetoidmovementsofthe faceaswellastheneckandtrunk.Whychronicdopaminergicblockadeshouldleadtothistypeof hyperkineticmovementdisorderisnotwellunderstood;postulatedmechanismsincludeupregulationof dopaminereceptorsoranimbalancebetweenthestimulationofdifferentclassesofdopaminereceptors.

Theoffendingmedicationsshouldbeimmediatelytaperedanddiscontinuedwhenpossible.Patients maygetbetteroveraperiodofmonths,althoughinsomethemovementdisorderwillpersist.Thesame drugsusedtotreatHuntingtondisease,aswellasdeepbrainstimulation,canhelpsomepatientswith tardivedyskinesia.Valbenazine,tetrabenazine,anddeutetrabenazine,VMATinhibitorsthatlimit monamine1vesiclepackagingandrelease(knowncolloquiallyasmonoaminedepleters),havebeen approvedforsymptomaticrelief.

Themonoamineneurotransmittersincludedopamine,epinephrine,norepinephrine,and

serotonin;VMATstandsforvesicularmonoaminetransporterandiscrucialinloading

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theseneurotransmittersintotheirtransportvesicles.

Dystonia

Dystoniaischaracterizedbythesustainedorintermittentinvoluntarycontractionsofmusclegroups resultinginabnormalposturesandisoftenassociatedwithuncontrolled,repetitivetwistingmovements. Theunderlyingpathophysiologyisnotwellunderstood.Therearemultipletypesofdystonicdisorders thataresubdividedbasedonthepartofthebodythatisaffected(generalizedvs.focal),etiology (inheritedvs.acquired),ageofonset,andotherassociatedfeatures.Althoughthedetailsofthese disordersarebeyondthescopeofthisbook,therearesomeessentialsyouneedtoknow:

Generalizeddystoniascanaffectmultiplepartsofthebody.Themostcommonistheresultofamutation

inthedystonia1gene.Wilsondisease(seepage344)canalsocausegeneralizeddystonia.

Focaldystoniasaffectonlyasingleregionofthebody.Amongthesearecervicaldystonia(affectingthe

neck;thisisalsoknownasspasmodictorticollis),blepharospasm(theeyelids),vocalcordspasmodic dystonia,andtask-specificdystonia(writer’scrampisacommonexample).

Treatmentwithanticholinergicagents,musclerelaxers(e.g.,baclofen),benzodiazepines,andlevodopa canbeeffective.Botulinumtoxininjectionsarealsousefuland,unliketheaforementionedoptionswhich areallassociatedwithsignificantsideeffects,haveeffectivelynosideeffects.

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Cervicaldystonia.Botoxisfirst-linetreatment.

Myoclonus

Myoclonusreferstosuddenlightning-likeinvoluntarymusclecontractions.Itcanarisefromnearly anywhereinthenervoussystemandhasmanydifferentcauses.Itcanbephysiologic,secondarytoan underlyingsystemicorneurologicdisorder,epileptic,oraprimarydiseaseuntoitself.

Hiccups(diaphragmaticmyoclonus)andhypnicmyoclonus(thesuddenjerkmanypeoplegetjustas theyarestartingtofallasleep)areexamplesofphysiologicmyoclonus.

Causesofsecondarymyoclonusincludehepaticandrenalfailure.Postanoxicmyoclonus,oftenseen inpost-cardiacarrestpatients,isalsocommon.Asterixis,aformof“negative”myoclonus,occursmost ofteninpatientswithadvancedliverdiseaseandisactuallytheresultofasuddenlossofmuscletonedue totheinterruptionofongoingmusclecontractions.

Whenmyoclonusarisesfromabnormalactivityinthecerebralcortex,itisconsideredepileptic(see page163).

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Essentialmyoclonusisthetermusedwhenthereisnoclearcauseorifmyoclonusissuspectedtohave ageneticbasis.Hereditaryessentialmyoclonus,forexample,isanautosomaldominantdisorder characterizedbyupperextremitymyoclonusthatimproveswithalcoholingestionandoccursinthe absenceofanyotherneurologicsymptoms.

Yourevaluationofmyoclonusbeginswithtakingagoodhistoryandperformingacomprehensive examination.Ifthecauseisnotobvious,furtherworkup,likelyincludingsomecombinationoflaboratory testing(acomprehensivemetabolicpanelwillcovermostmetabolicpossibilities),drugscreening,brain imaging,andEEG,shouldbeconsideredonacase-by-casebasis.

Treatmentinvolvescorrectinganyunderlyingreversiblecauses,identifyingandtreatinganyseizure disorder,andsymptomatictherapywithanticonvulsantsorbenzodiazepines.

TicDisordersandTouretteSyndrome

Ticsarerapid,repetitiveinvoluntarymovementsorsounds.Motorticsarethemostcommontypeoftic (theymaybesimple,suchassinglerepeatedmovementsresemblingmyoclonicjerks,orcomplex, involvingawholesequenceofmovements).Verbalticsandvocalizationsincludethroatclearing, coughing,andcoprolalia(utteringobscenities).Patientstypicallyfeelapremonitoryurge,often unpleasant,toticandgetreliefimmediatelyafterward.Brief,voluntarysuppressionoftheticisoften possiblebutcannotalwaysbesustained.

Mostticsstartinchildhoodand,inamajorityofpatients,resolveinadulthood.Tourettesyndromeis characterizedbybothmotorandvocaltics;thediagnosisrequiresthepresenceofatleastonemotortic andonevocalticoccurringbeforeage18years.Itistheresultofacombinationofmultiplegenetic mutations.Theunderlyingpathophysiologycontinuestobeinvestigated.Symptomscanbemildorsevere. Frequentcomorbiditiesincludeattentiondeficitdisorder,obsessivecompulsivedisorder,andmood disorders.Patientsmayalsoexperiencedisruptedsleepanddifficultiesatschool.

Treatmentdependsontheseverityofthesymptoms.Somepatientsrequirelittlemorethanreassurance. Whenticsaredisabling,aformofbehavioraltherapycalledhabitreversaltrainingisfirst-line management;thistechniqueincorporatesawarenesstraininganddevelopingcompetingresponses.Ifthis therapyisnotavailableorifsymptomspersist,medicationstoconsiderincludedopaminedepleters (tetrabenazine),antipsychotics(risperidone),andalpha-adrenergicagonists(guanfacine,clonidine). Botulinumtoxin,forfocaltics,anddeepbrainstimulationcanalsobehelpful.Symptomstendto significantlyimproveifnotentirelyresolvebyadulthood.

Sleep-RelatedMovementDisorders

Wehavealreadymentionedhypnicmyoclonus,themyoclonicjerksthataccompanyfallingasleepor transitionsfromonestageofsleeptoanother.Thisconditionisbenignandrequiresnofurtherevaluation ortreatment.

Restlesslegssyndromeischaracterizedbyanunpleasantsensationtomoveone’slegs,usually occurringatnightinbed.Acrawlingoritchingsensationinthelegsisalsocommon.Gettingupand movingaroundrelievesthesymptoms.Somepatientsmayhavealowserumironlevel,andallshould havetheirserumironandferritinmeasured.Othercausesincludeuremia,pregnancy,andvarious medicationsandothersubstances(commonculpritsincludeantihistamines,nicotine,caffeine,and alcohol).Inmostpatients,nounderlyingcorrectablecausewillbefound.Treatmentshouldfocuson

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stoppinganypotentialoffendingmedicationsandsubstancesandencouragingregularexercise.Ifyour patientwantstotrypharmacologictherapy,gabapentinanddopamineagonistscanbehelpful.Patients withlowferritinlevelsoftenrespondtoironreplacementtherapy.

Therearenumerousothersleepdisordersassociatedwithabnormalmovements.Twoinparticular deservemention,bothofwhichcanbediagnosedwithpolysomnography:

Periodiclimbmovementsofsleepisadisordercharacterizedbyflexionmovementsofthelegsthat repeatin20-secondcycles. REMsleep behavior disorder(RBD) occurs inpatientswholose thenormal sleep paralysis that occursduringtheREMstageofsleep.Theythereforeactout theirdreams,ofteninviolentfashion with kicking and punching. It appears to respond well to both high-dose melatonin (first-line treatment) and clonazepam. REM sleep behavior disorder is often a prodromalsymptom ofalpha synucleinneurodegeneration, and thus most patients with RBD will ultimately develop Parkinson diseaseoroneoftheotheralphasynucleinopathies.

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