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1/30/18
1
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