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DRUG-INDUCEDMOVEMENTDISORDERS

PilleTabaMD,PhDUniversityofTartu,Estonia

4February2018,Bordeaux

MDS-ESWinterSchoolforYoungNeurologists

Etiologyofmovementdisorders

Neurodegeneration

Geneticfactors

Immunemediated

Metabolic

Toxicanddruginduced Traumatic

Vascular Infections

Psychogenic

Druginducedmovementdisorders

•  Parkinsonism

–  Subacute–  Symmetrical

–  Historyofmedications!

–  Akineticrigid–  Tremor:atypical,postural

–  Accompanyingoral-buccaldyskinesiasorakathisia

•  Dystonias,dyskinesias•  Chorea•  Akathisia•  Myoclonus

•  Tics•  Tremor

DRUGSinducingmovementdisorders

•  Neuroleptics–  Butyrophenones

(haloperidol,droperidol)–  Phenotiazines

(chloropromazine,thioridazineetc)

–  Atypicalneuroleptics(risperidone)

–  Benzamids(metoclopramide)

•  Dopaminedepletors–  Reserpine–  Tetrabenazine

•  Ca-channelblockers–  Cinnarizine–  Flunarizine

•  Anticonvulsants–  Valproate–  Phenytoin

•  Antidepressants–  Tricyclic–  SSRI

•  Antihistamines

•  Antiarrhytmics

•  LithiumMehta et al. Neurol Clin 2015

Malek N, Baker MR. Postgrad Med J 2017

Tardivedyskinesia

•  In15-30%ofpatientsonlongtermantipsychotictreatment

•  Classictardivedyskinesia–  Orofacial/bucco-lingual–  Limbs,trunk

–  Rarerlyrespiratory•  Variants

–  Tardivetourettism

–  Tardivemyoclonus

–  Tradivetremor

•  Higherriskinfemale;olderage

Cornett et al, Ochner J 2017

Video

Malignantneurolepticsyndrome

Majorcriteria•  Hyperthermia•  Musclerigidity

•  Increaseofcreatinekinase(CK)

Minorcriteria•  Changesinmentalstatus

–  Alteredconsciousness–  Delirium,agitation

•  Dysautonomia–  Tachycardia–  Unstablebloodpressure–  Tachypnoea–  Profusesweating,

sialorrhoea–  Leucocytosis

Confirmeddiagnosis:

1)  All3majorcriteria

2)  2majorand4minorcriteria

Iatrogenic:dopaminereceptorblockers/antipsychotics;rarely–endofantiparkinsonianmedication

Levenson Criteria 1985; DSM-5 Criteria 2013

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Malignantneurolepticsyndrome

•  Treatment:Dantrolen.Bromocriptine,benzodiazepines

•  Rehydratation,hypothermia

•  Longtermcomplications–  Parkinsonism

–  Tardivedyskinesias–orobuccal,tongue–  Dystonias–  Cerebellardegeneration–  Peripheralneuropathy–  Contractures

Serotoninsyndrome

•  Causedbydrugsenhancingserotonergictransmission–  MAOinhibitors(MAO-Binhibitorsveryrarely)–  Selectiveserotoninreuptakeinhibitors(SSRI)–  Tricyclicantidepressants–  Opiates,amphetamines,MDMA(ecstasy),cocaine

–  ..•  Coreclinicalfeatures

–  Fever,tachycardia,hypertension,diarrhea–  Myoclonus,opsoclonus,tremor,rigidity,seizures

–  Alteredmentalstatus,anxiety,agitation,delirium

Wang RZ et al. Clev Clin J Med 2016

Video

Druginducedparkinsonism

•  Etiology–  Neuroleptictreatmentsinpsychiatricpatientson–  Metoclopramide–  Reserpine,tetrapenazine–  Cinnarizine,flunarizine

•  Higherrisk:olderage;women•  Mayworsendespiteofwithdrawalofthecausingmedication•  DifferentiatingfromPD:

–  Non-motorsymptoms–inPDmoreurinarysymptoms,sleepdisorders,hyposmia

–  SPECTnormalindruginducedparkinsonism,abnormalinPD–  1231-MIBGscintigraphynormalindruginducedparkinsonism,

abnormalinPD

Brigo F et al. Parkinsonism Relat Disord 2014

Levodopamotorcomplications:Community-basedandopenstudies

Studysite Authors L-dopayears

Motorfluct%

Dyskinesias%

Tartu,Estonia Kadastiketal2017 5 20 21

Norway Bjornestadetal2016 5 43 24

Aberdeen,UK Scottetal2015 5 21 28

Malaysia Hashimetal2014 3 50 44

Madrid,Spain Lopezetal2010 3 23 25

10 94 71

HongKong Kumetal2009 5 75 78

Istanbul,Turkey Benbiretal2006 6.5 46 30

Sydney,Australia Helyetal2005 15 96 94

London,UK SchragandQuinn2000 5 40 28

Dehli,India DennyandBehari1999 3 50 25

Madrid,Spain Grandasetal1999 4 44 64

Kansas,USA Miyawakietal1997 0-5 24 13

>15 70 72

London,UK Poeweetal1986 6 52 54

Medicationinducedtremor

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

patient with postischemic Holmes tremor respondeddramatically to 1000 mg/day levetiracetam [79,80].Three additional case reports have been publishedsince 2009 with deep brain stimulation (DBS). In thefirst report, Holmes tremor occurred secondary toa cystic degeneration of the brainstem and wassuccessfully treated with contralateral ventralisintermedius nucleus (VIM) stimulation of thethalamus [81]. In a second patient, who developedHolmes tremor after a subarachnoid hemorrhage,bilateral VIM stimulation suppressed both bilateralupper extremities and orolingual tremor [82]. Ina third case of a patient with hemicerebellarinfarction-induced Holmes tremor, stimulation ofthe ventro-oralis posterior nucleus and the zonaincerta abolished rest and postural tremor [83].

Drug-induced tremorCommonly described drugs that induce tremor aresummarized in Table 1 [84]. In a recently publishedarticle five of 216 patients receiving itraconazoleover a 20-month period developed a clinicallyheterogeneous 4–6 to 12–15 Hz rest tremor [85].

Orthostatic tremorClassical orthostatic tremor presents with uncertainstance and a 13–18 Hz tremor in the leg muscles. Anew variant called slow orthostatic tremor witha frequency of less than 12 Hz was described inParkinson’s disease [86] and patients with cerebellar

lesions [87]. Idiopathic orthostatic tremor is termedprimary orthostatic tremor. Additional neurologicalfeatures in 25% of patients are referred to as ‘ortho-static tremor plus’. Treatment is a challenge andincludes gabapentin, clonazepam, primidone andphenobarbital [88]. Levetiracetam in a dosage upto 3000 mg/day was studied in 12 orthostatic tremorpatients using a double-blind crossover design, andwas found to be ineffective [89]. Nonpharmaco-logical treatments have included mechanical aidsincluding portable stools [88].

Task specific tremorPrimary writing tremor (PWT) is considered a task-specific pronation/supination tremor that occursduring a pronated hand-held position while writing[90&]. Type A PWT (task induced tremor) occurs onlyduring writing, whereas Type B (positional sensitivetremor) arises during pronation of the hand also inother tasks [91]. PWT been considered either as avariant of essential tremor, a type of focal dystoniaor a separate nosological entity. Pharmacologicaltreatment includes propranolol, primidone, anti-cholinergics or botulinum toxin [90&,92]. A writingdevice has successfully been introduced in ninepatients [75], and case reports employing thalamicdeep brain stimulation produced good improve-ment. High frequency transcranial electrical nervestimulation (TENS) at 5 and 25 Hz failed to improvePWT; indeed, at 50 Hz stimulation worsened tremorand associated excitability [93,94].

Table 1. Medication induced tremor

Group Medication Tremor character

Antiarrhythmic Amiodarone Clinically similar to essential tremor, 6–10 Hz action tremor

Antidepressant Tricyclic, serotonin re-uptake inhibitor,monoamineoxidase inhibitor

Generalized action tremor, 6–11Hz

Beta adrenergic agents Terbutaline, metaproterenol, isoetharine,epinephrine, adrenaline

Rest and action tremor, low amplitude and high frequency

H2 antagonist Cimetidine Action tremor 8–12Hz

Calcineurine inhibitor Ciclosporine A Generalized action tremor, rarely cerebellar tremor;treatment with propranolol

Anticonvulsant Lamotrigine Postural and action tremor

Valproate sodium Rest and postural tremor

Neuroleptics Lithium Irregular, not rhythmic tremor in arms/legs; treatmentwith primidone/ß-blocker

Antipsychotics Low- and high potent (i.e. Haloperidol,Clozapine)

Rest and postural tremor 4–7 Hz; tardive tremor aspostural tremor 3–5 Hz; asterixes

ß-adrenergic Inhibitors Pindolol Low amplitude, high frequency tremor

Antiobstructive agent Theophylline High frequency, low amplitude postural tremor

Triazole antifungal agent Itraconazole Heterogeneous, from 4–6Hz to 12–15 rest tremor

Data from [84].

An update on tremors Zeuner and Deuschl

1350-7540 ! 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-neurology.com 479

Zeyner KE, Deuschl G. Curr Opin Neurol 2013

Drugs–analgesicsandanesthetics

MEPERIDINE(pethidine)

•  Opioidforpaintreatment

•  Rarelyreported

–  Tremor,myoclonus,seizures–  Agitation,hallucinations

•  Acaseofreversibleparkinsonismdescribed

METHADONE

•  Syntheticopioid

•  Treatmentofpainandopioiddependence

•  Causesrarelychoreaortremor

PHENCYCLIDINE

•  Anesthetic,similartoketamine

•  Eaten,snortedorinjectedinrecreationalpurposes

•  Agitation,psychosis•  Rigidity,dystonia,athetosis,

ataxia,myoclonus

γ-HYDROXYBUTYRICACID(GBH)•  Usedfortreatmentofnarcolepsy

andasageneralanesthetic•  Recreationaldrug

•  Overdose:myoclonusandseizures•  Withdrawal:choreaandtremor

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ILLICITDRUGS

Amphetamine-related

•  Amphetamine(Amph)

•  Methamphetamine(Meth)

•  Methylene-dioxy-meth-amphetamine(MDMA/ecstasy)

•  Methylphenidate

•  Cathinone(Khat)

•  Methcathinone(Mcat)

•  Mephedrone,methylone,buthylone,naphyrone,...

Other

•  Cocaine

•  Heroin/heroinpyrolysate

•  1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine(MPTP)

•  Methadone

•  Meperidine

•  γ-hydroxybutyricacid•  Toluene

Chemist’sNotebookManual–receiptsinInternet

•  Methamphetamine–CrystalMeth,Speed

•  Methcathinone–Cat,Jeff•  GHB–LiquidE,DateRapeDrug

•  MDMA–Ecstasy,X

•  Phencyclidine–PCP,AngelDust

•  Cocaine–Coke,Blow

•  Opiates–Heroine,Codeine•  Marijuana–Weed,Bud•  Psilocybin–Shrooms,Caps•  SalviaDivinorum–DreamHerb,Salvia

•  DMT&5-MeO-DMT–ToadVenom

•  Ketamine–SpecialK•  Dextrometorphane–DXM,RedDevil’s

History:MPTP(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)andparkinsonism

•  Usedin1980iesinCaliforniaintra-venouslyasanew“syntheticheroin”

•  By-productinthesynthesisofMPPP

•  Parkinsonism-duringsomemonths

•  SimilartoParkinson’sdisease:–  Rigidityandhypokinesia

–  Gaitdisorder;speechdisorder

–  Rarelytremor

–  Hallucinationsoftenasinitialsigns

–  Levodopatreatmenteffective

–  Earlydyskinesiasand‘on-off’fluctuations Video: A J Lees/ JW Langston

Langston JW et al. Science 1983;219:979-80

Video

NumberofpublicationsavailableinPubMedAsser A et al. Front Neurol 2015:75

GlobalDrugSurvey

Useofpsycostimulants

80000responsesreporteduseduringthepast12months:

•  23.7%MDMA(“ecstasy”)•  16.4%cocaine•  11.7%amphetamine•  7.5%“researchchemicalsand

legalhighs”(bathsalts)

www.globaldrugsurvey.com

Video

Amphetamines•  Increaseofdopamine,norepinephrineandserotoninerelease

•  Amphetamine–synthesisedin1887inGermanybyLazarEdeleanu;pharmacologicalusein1929byGordonAlles

•  Usedfortreatmentofnarcolepsy,attentiondeficitehyperactivitydisorder,obesity,chronicfatigue

•  Agitation,confusion,psychosis•  Levo-anddextroisomers

Highdosage–neurotoxicFreeradicals

Excitotoxicity

Apoptosis

Mitochondrialdysfunction

Neurodegenerationaffectingbasalganglia

Neuronalloss

Reductionofglialastrocytes

Changesinmicrovasculature

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Amphetamineandmethamphetamine

•  Increaseofdopamine,norepinephrineandserotoninerelease

•  Methamphetamine–synthesisedfromephedrinein1893•  Amphetamine–synthesisedin1887;pharmacologicalusefrom

1929byGordonAlles:–  Narcolepsy,attentiondeficithyperactivitydisorder,obesity,fatigue

•  Movementdisordersmaydevelopduringabuseorabstinence

•  Choreoathetosis,tremor,dystonia,araxia,gaitdisturbances•  Usuallyresolvewithinfewdaysbutmaylastlonger

•  Bensodiazepinesoreurolepticsmaybeofbenefit

Metamphetamine/Amphetamineandparkinsonism?

•  ArechronicMeth/Amphusersatrisktodevelopparkinsonism?

•  Dothechangesreflectdegenerativedisorder,orareinducedbythedrugtoxicity?

•  -but•  Clinically,parkinsonismhasnotbeendescribed

•  ReductioninDATdensityisdifferentfromParkinsondisease–lessextentinputamen

•  -still•  Population-basedcohortstudyinCalifornia(1990-2005):Meth/

AmphusershaveincreasedriskforPDbutnotcocaineusers

Callaghan RC et al. Drug Alcohol Dependence 2012;120:35-40 McCann UD, et al. J Neurosci 1998;18:8417-22

CaseEcstasyandparkinsonism?

•  38yearsman•  Heavyuseofecstasyfor12years

•  Rapidlyprogressiveparkinsonism

•  PooreffectofmedicationandDBS

•  19yearsman

•  Used6monthuseofMDMA

•  Tremorandparkinsonism•  Antiparkinsonianmedication-

pooreffect

O’Sulleabhain P, Giller C. Mov Disord 2003;18:1378-1403 Kuniyoshi SM, Jankovic J. New Eng J Med 2003;349;96-7

Video: P O’Sulleabhain 2003

Video

Methylphenidate(MPH,MPD)

•  Psychostimulantusedforthetreatmentof–  Attention-deficithyperactivitydisorder(ADHD)–  Narcolepsy–  Posturalorthostaticsyndrome

–  Weightcontrol

•  Recreationaldrug•  Mayinducechorea,tics,dyskinesias

•  BritishNationalFormula(2011:p.246)–  Indications:ADHD,narcolepsy(adultandchildren)–  Side-effectsofMPH:tics,movementdisorders

Methcathinone/ Ephedrone Metamphetamine

Pseudoephedrine

Cathinone Amphetamine

Ephedrine

Methylone; Mephedrone; Bythylone

Methcathinone(Mcat)/ephedrone

•  Usedasantidepressant1930-1940•  Amphetamine-likeeffect•  Abusedasa‘designer’psychostimulant

–  Sudafedtablets(pseudoephedrine)–  Boilingwater–  Potassiumpermanganate–  Aceticacid

•  10-20injectionsperday•  Estimateddailyloadof

–  manganese:60-180mg–  Mcat:400-1200mg

Sikk K et al. Int Rev Neurbiol 2015;120:257-272

Video

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Mcatabusersandmanganism

•  Clinicalsyndromedevelopsduringmonths-years−  Parkinsonism:bradykinesia

−  Limbandfacedystonias

−  Dysarthria,hypophonia

−  Gaitdisorder,posturalinstability,falls

•  Severityvariesgreatly•  Unreponsivetolevodopa•  Mayworsendespitedrugdiscontinuation

Video

Cocaine

•  Alkaloidcoca-plantleaves–SouthAmericanindigenouschewed

•  Describedinthe16thcentury;isolated1855byGermanchemistFriedrichGaedcke

•  Neuropathologicalinvestigation:α-synucleinlevelsinDAcellselevated

‘Crackdancing’–smokablesocaine•  Inchroniccocaineabuse•  Reversiblechoreiformlimbmovementsorakathisia•  Orofacialdyskinesias•  Rarely:neurolepticmalignantsyndromefollowingtodelirium

Neurologicalcomplicationsofpsychostimulants

Chemical Neurologicaladverseeffects

Amphetamine Tremor,choreoathetosis,dystonias,ataxua,gaitdisordreIschaemicinfarction,intracerebralhaemorrhage

Methamphetamine Choreoathetosis,dystonias,tremor,ataxia,seizuresBehaviouraldisorders,psychosis,depression;Stroke

MDMA(Ecstasy) Tremor,dystonias,parkinsonism,restlesslegs;SeizuresCognitivedysfunction

Methyphenidate Anxiety,hyperactivity,stereotypicalmovements

Cathinone Tremor;Memorydisorder,depression,psychosis,insomniaIntracerebralhaemorrhage

Mephedrone Tremor,myoclonus,choreopthetosis;CognitivedisorderCerebraloedema,seizures

Methcathinone Parkinsonism,dystonias,speechdisorder,posturalinstability,falls

Cocaine Tremor,tics,dystonias,parkinsonism,chorea,akathisiaSeizures;Stroke

Heroin

Intravenousheroin

•  Euphoriafollowedbydream-likestate•  Overdose

–  coma,respirationdepression

–  brainanoxia,ischaemia

•  Borderzoneinfarction–  Tremor,rigidity,myoclonus,dystonias,

ballism,ataxia,cognitiveimpairment,oculogyriccrises

•  MRI:graymatterlesioninbasalganglia

•  Section:bilateralcysticinfarctsingl.pallidum

Heroinpyrolysate-‘chasingthedragon’

•  Heroinepyrolysate‘chasingthedragon’–inhalation,heatingthedrugonmetalfoil

•  Spongiformencephalopathy–  Ataxia,dystonia,myoclonus,chorea–  Apathy,confusion–  Spasticparaparesisortetraparesis–  Pseudobulbarpalsy–  Latestages–parkinsonism

•  Neuropathology–  Spongiformdegenerationofdeepwhite

matter–  Vacuolisation,lossofoligodendrocytes,

axonalreduction,astrogliosis

Plantswithpsychedeliceffects•  Peyotecactus(Lophophorawilliamsii)

–  Containsmescaline–  Dyskinesia,chorea

•  Angeltrumpetflower(genusDatura)–  Containstropanealcaloids–  Blurredvision,speechdisorder,hallucinations–  Chorea,ballism,ataxia,seizures

•  Kavakava(pipermethysticum)–  Containskavapyrones–  CeremonialbeverageinthePacificandAustralia–  Musclerelaxation,anaesthesia,anxiolytic–  Choreoathetosis,dystonias,parkinsonism

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Conclusions

Drug induced movement disorders can represent MEDICAL EMERGENCIES

•  Neuroleptic malignant syndrome •  Serotonin syndrome

• Toxic conditions due to illicit drugs

Variable phenotypic manifestations Suboptimal treatment

•  No preventive treatments •  The most important – avoiding exposure

•  Amanitamuscaria

•  Hallucinogens:muscimol,ibotenicacid

•  OswaldSchmiedeberg-DeptofMateriaMedicainTartu,1847-1867–  Describedmuscarineanditsantagonismwithatropine–abasisfor

thetheoryaboutantagonismofpoisonsandantidotes–  Provedthatnerveendingscanbepharmacologicallyselectively

influenced:foundedpharmacologyofsynaptictransmission