Objective of this paper is to review drug-induced movement disorders (D-IMD) treated patients on Department of Neurology in University Hospital Osijek. We reviewed patients treated during 10 years period (from 1992 to 2002). Analysed group consisted of 14 patients. Reasons for hospitalisation were swallowing problems in 6 patients, neuroleptic malignant syndrome (NMS) in 3 patients, stroke in 2 patients, bolus choking in 2 patients, and speech disturbance in 1 patient.Working diagnosis for most of our patients was neurological disease, yet only later D-IMD diagnosis was established excluding primary neurological disease, or as associated disease to basic neurological disorder. Nine patients have diagnosed as Parkinson syndrome, 3 patients as NMS, and 4 as orolingual dyskinesia, either autonomously, or in combination with Parkinson syndrome. D-IMD was most frequently caused by neuroleptics. Thus the small number of patients hospitalised regarding this syndrome on Department of Neurology

Damir Štimac

Lidija Knežević

Ružica Palić

Silva Butković-Soldo

Stjepan Jurić

Svetlana Tomić

English

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Coll. Antropol. 29 (2005) 2: 579–582UDC 616.89-085(497.5Osijek)''1992/2002''Original scientific paperPatients Review: Drug-InducedMovement DisordersSilva Butkovi}-Soldo1, Svetlana Tomi}1, Damir [timac2, Lidija Kne`evi}1, Ru`ica Pali}1, Stjepan Juri}1and Ksenija Marijanovi}31 Department of Neurology, University Hospital Osijek, Osijek, Croatia2 Department of Radiology, University Hospital Osijek, Osijek, Croatia3 Department of Pathology, University Hospital Osijek, Osijek, CroatiaA B S T R A C TObjective of this paper is to review drug-induced movement disorders (D-IMD) treated patients on Department ofNeurology in University Hospital Osijek. We reviewed patients treated during 10 years period (from 1992 to 2002).Analysed group consisted of 14 patients. Reasons for hospitalisation were swallowing problems in 6 patients, neu-roleptic malignant syndrome (NMS) in 3 patients, stroke in 2 patients, bolus choking in 2 patients, and speech distur-bance in 1 patient. Working diagnosis for most of our patients was neurological disease, yet only later D-IMD diagnosiswas established excluding primary neurological disease, or as associated disease to basic neurological disorder. Ninepatients have diagnosed as Parkinson syndrome, 3 patients as NMS, and 4 as orolingual dyskinesia, either autono-mously, or in combination with Parkinson syndrome. D-IMD was most frequently caused by neuroleptics. Thus thesmall number of patients hospitalised regarding this syndrome on Department of Neurology.Key words: drug-induced movement disorders, Parkinson syndrome, orolingual dyskinesia, neuroleptic malignantsyndrome, neurologyIntroductionThe objective of the paper is to study drug-inducedmovement disorders (D-IMD) treated patients on De-partment of Neurology in University Hospital Osijekduring a ten-year period in order to show possible clini-cal manifestations of the syndrome and to investigatethe reasons for D-IMD patients’ hospitalization on De-partment of Neurology, since most frequent D-IMD cau-se is neuroleptic therapy, and therefore this disorder isin the domain of Department of Psychiatry.Drug-induced movement disorder is neurologic moto-ric disturbance caused by drugs. Its features are: abnor-mally increased motor activity, impaired back posture,abnormally decreased motoric function, mobility andposture. It may be persistent or reversible1. The mostcommon form is Parkinson syndrome, characterized bybradykinesia, rigidity and tremor2. Tardive dyskinesia,akathisia, ticks and dystonia may also be found as partof the syndrome3,4,5. The most severe manifestation isneuroleptic malignant syndrome (NMS) – characterizedby severe rigidity, akinesia, hyperthermia, autonomousdisturbances, and changes in serum: leukocytosis, ele-vated sedimentation rate, increase of creatinin-phos-phokinase and liver enzymes levels)3,4.Simultaneous use of different neuroleptics, depotdrugs, concurrent lithium therapy, organic brain dam-age, dehydration and excessive heat exposure and malesex are higher risk factors for NMS3. In general, older,as well as female patients, have more chances to de-velop D-IMD. It is suspected that there is a hereditarypredisposition for D-IMD too6.It is well known that many drugs may cause D-IMD,but some of them are more often charged as guilty forthis syndrome. The most common cause of D-IMD isneuroleptic therapy, more often typical neuroleptics incomparison to atypical ones. However, levodopa prod-ucts, drugs that empty dopamin pools, sedatives, cal-cium channel blockers, MAO inhibitors, natrium channelblockers, cytostatics, antimycotics, selective serotoninreuptake inhibitors, cholinesterase inhibitors, lithiumcarbonate and antiepileptics may cause this syndromeas well7–11.579Received for publication September 23, 2004Division to typical and atypicial neuroleptics is fo-unded on several factors, among which the most impor-tant is affinity toward dopamine D2 system. The affinitytoward dopamine D2 system is less prominent in atypi-cal neuroleptics, causing smaller frequency of extra-pyramidal side effects.Duration of D-IMD causing therapy, as well as dailyneuroleptic doses aren’t correlated with appearance ofD-IMD6. It is considered that real cause of extrapyramidsymptoms is not only block of dopaminergic receptors,but possible toxic basal ganglia effect is suspected12.Some of these patients, especially those with NMS arelife endangered due to possible myocardial infarction,aspiration pneumonia or rhabdomyoliysis with acute re-nal insufficiency3. Therefore it is very important to sus-pect and establish correct diagnosis in order to startproper therapy on time and prevent letal outcome.Therapeutic approach consists of terminating drugsthat are suspected to cause the syndrome, bearing inmind higher risk of worsening symptoms of basic psy-chiatric disease, use of anticholinergic drugs, and some-times small doses of dopaminomimetic agents7.Parkinson syndrome usually diminish after the ther-apy, although, symptoms may persist in some patientsin spite of treatment. It is supposed that they had latentor subclinic form of Parkinson disease which manifestedafter the neuroleptics therapy13,14 due to additional ef-fect on basal ganglia.Materials and MethodsPatients treated on Department of Neurology in Uni-versity Hospital Osijek which had diagnosis of drug-in-duced movement disorders were analyzed during 10years period (from year 1992 to 2002). University hospitalOsijek is regional hospital for the East Slavonia andBaranja district. Our hospital covers population of 300,000people, while the rest of East Slavonian population iscovered by general hospitals in Vukovar and Vinkovci.All of our patients come from district of City of Osijekand surroundings.Disease data were retrieved from patients’ records onbasis of hospital treated patients index on Departmentof Neurology. Patients were found in our index regard-ing discharge letter diagnosis of D-IMD. All the in-hos-pital patients met the criteria we’d set, and thereforenone of them were excluded from the study. Only dis-charge letter from the Department of Neurology was re-viewed per patient during the study period in order toassess the necessary data. Follow-up timeframe was upto patients discharge from the Department of Neurol-ogy. Not a single of these patients had more than onehospitalisation on the Department of neurology regard-ing these disorders. Ambulatory checked and treatedpatients weren’t included in the examination.Diagnoses of drug-induced movement disorders weremade on basis of anamnestic data, neurologic and physi-cal examination and laboratory findings.Among anamnestic data we searched for suspecteddrug-induced movement disorders therapy use and du-ration of that kind of a treatment. Neurological exami-nation revealed extrapyramid symptoms and signs suchas rigidity, bradykinesia, tremor and orolingual dyski-nesia. Hyperpyrexia and autonomous disorders (bloodpressure and heart rate disorder) were found during thephysical examination. Laboratory findings revealed ele-vated sedimentation rate, increase in leukocytes num-ber, creatinin-phosphokinase and liver enzymes levels.Reasons for D-IMS patients’ hospitalisation and clin-ical manifestation of extrapyramide syndrome were an-alyzed, as well as medicamentous therapy that patientsused and which could have caused this syndrome, andtime duration from beginning of therapy to extrapyra-midal symptoms onset. We studied length of hospitali-sation, disease therapy during hospitalisation, course ofdisease and its final outcome.ResultsExamined group consisted of 14 patients; 8 of themfemale, 6 male. Average age was 70, 74 in female group,and 69.7 in male, in the range of 55 to 80 (female 55 to80, male 64 to 75).Reasons for hospitalisation were swallowing prob-lems (6 patients), malignant neuroleptic syndrome (3patients), cerebrovascular infarction (2 patients), boluschoking (2 patients), and speech disturbance (1 patient).In discharge letter 9 patients had diagnosed as Par-kinson syndrome, 3 patients as NMS, and 4 as oro-lingual dyskinesia, either autonomously, or in combina-tion with Parkinson syndrome.Used drugs analysis showed that D-IMD was mostfrequently caused by neuroleptics; typical ones: flu-fenazin and haloperidol used 7 patients, promazine 5patients, and sulpirid used 1 patient; and atypical ones:clozapin used 2 patients, and 1 patient used olanzapin.Most patients, 5 of them, had monotherapy treatment, 4patients used two neuroleptics simultaneously, and 4patients used three kinds of neuroleptics at the sametime. Considering other groups of drugs, DIMD was alsocaused by levodopa in 1 patient, and metoclopramid in 1patient.D-IMD presented with different symptoms: 9 pa-tients had Parkinson syndrome, 3 patients had NMS,and 4 patients had orolingual dyskinesia either autono-mously, or in combination with Parkinson syndrome.Time of duration of therapy untill symptom onsetranged from 10 days to 22 years. 3 patients developedsymptoms in period from 0 to 1 year of drug usage, 5 pa-tients in period of 2 to 10 years, and 3 patients in period11 to 20 years, and 1 patient in period longer than 20years. Data of duration of therapy usage before onset ofsymptoms remained unknown for 2 patients.During the hospitalisation patients were treated byterminating incriminated drugs therapy, infusion, bipe-ridin, levodopa products and sedatives.S. Butkovi}-Soldo et al.: Drug-Induced Movement Disorders, Coll. Antropol. 29 (2005) 2: 579–582580Basic psychiatric disease had worsened in 4 patients,5 patients presented no changes in extrapyramidale(EP) symptomatology, and decrease of EP symptomswas noticed in 2 patients, while 3 patients fully recov-ered. Average hospitalisation duration was 14.9 days, inthe range of 3 to 24 days. 11 patients were dischargedafter the end of treatment, 2 patients were transferredto other departments for further treatment, and 1 pa-tient died.DiscussionAlthough many drugs may cause extrapyramide sideeffects, neuroleptics are the most often cause of D-IMD.Thus the small number of patients hospitalised regard-ing this syndrome on Department of Neurology. Work-ing diagnosis for most of our patients was neurologicaldisease, yet only later D-IMD diagnosis was establishedexcluding primary neurological disease, or as associateddisease to basic neurological disorder. Patients withcerebrovascular infarction had reason for hospitaliza-tion on our Department. Later on, during their stay onour department we found out that they also have hadthe symptoms of drug-induced movement disorders (notrelated to CVI). Patients with neuroleptic malignantsyndrome were hospitalised due to life threatening stateand it's emergency on Department of Neurology.During the almost same time interval (year 1993 to2002) 45 patients were hospitalised on Department ofPsychiatry University Hospital Osijek with D-IMD di-agnosis5.D-IMD is more often correlated with typical neuro-leptics use during psychiatric disorders treatment5,15–18.Some authors found 30% prevalence of tardive dyskinesiain psychiatric patients using neuroleptics20, while otherauthors published frequency of 40.6% and 29%2,17–19.Most of our patients had typical neuroleptics in theirtherapy protocol. Therapy protocol analysis showerdthat majority of them had two or three neuroleptics atthe same time, while only fewer number of patientswere on monotherapy. In case patient had been usingjust one drug in its therapy, the anamnestic data ex-posed potential movement disorder causing drug. Oth-erwise, if more than one neuroleptic was included in pa-tient’s treatment, it was impossible to assert the rightdrug that induced the movement disorder.It is considered that D-IMD begins as a result of D2receptor block. However, besides D2 receptors effect,some authors believe that D-IMD develops due to me-dicamentous toxic effect on basal ganglia12,21. Thus themaintenance of Parkinson syndrome after terminationof D-IMD inducing therapy can be explained. Some au-thors proved correlation between tardive dyskinesia on-set and genetic precondition7,22,23.D-IMD is one of many factors that should influencetherapy choice in psychiatric patients. Atypical neu-roleptics are generally preferred to typical ones due toless extrapyramidal symptoms coincidence, as well asantidyskinetic effects in patients with tardive dyski-nesia18,24,25.Pisa syndrome (rare type of truncal dystonia), sort ofD-IMD presentation, develops more often in patientswhom had an additional neuroleptic therapy introdu-ced, or patients with increased dosage of neuroleptic4.Some authors find correlation between daily neurolepticdose or depot neuroleptic product use and tardive dys-kinesia26, while other authors deny such correlation7.Our data showed that older patients are more proneto development of D-IMD, which is confirmed by otherauthors7,15,17,26. We haven’t been able to analyze neitherfrequency, nor statistical importance of this disorderconsidering sex due to small number of patients in ourreview, although some authors showed not only correla-tion between DIMD and age and organic injury, but tofemale sex as well4,7.Most of our patients developed D-IMD after 2 to 10years of therapy. The same number of patients usedtherapy less than one year; and more than 11 years, yetless than 20 years. Hall et al. didn’t find correlation be-tween therapy duration and D-IMD6.During hospitalization our patients were treatedwith anticholinergic agents (biperidine), the ones otherauthors found successful in D-IMD treatment too4,5,18,20.Drugs caused dystonia diminished after anticholinergicagent therapy only in 40% of cases, while the same ther-apy showed better results in cases of symptoms of idiopa-thic dystoniae4. We also used infusion, levodopa prod-ucts and sedatives, while D-IMD inducing drugs therapywas terminated. In some cases clozapin was proved assuccessful therapy in tardive dyskinesia treatment24.Effect of donezepil, a cholinesterase inhibitor, used indementia treatment is being studied27.Current D-IMD therapy model results are still un-satisfactory. It is noticed that there are always differ-ences in therapy response between two different clinicalD-IMD manifestations. Reports show that tardive dys-kinesia is much less responsive to therapy than dys-tonia4.Most of our patients showed progression of psychiat-ric symptoms, or no regression of extrapyramidal symp-toms at all, during the treatment. Only less number ofpatients fully recovered, or showed decrease of D-IMDsymptoms. One third of patients had dyskinesiae evenone year after ending of neuroleptic therapy28. Tardivedyskinesia treatment discouraging, therefore it empha-sizes prevention of this syndrome by carefully choosingatypical neuroleptic29, or, switching from typical to atyp-ical neuroleptics in case of already developed extra-pyramidal symptoms30.S. Butkovi}-Soldo et al.: Drug-Induced Movement Disorders, Coll. Antropol. 29 (2005) 2: 579–582581R E F E R E N C E S1. CHOUINARD, G., J. Clin. Psychiatry, 65 (2004) 9. — 2. STEPH-EN, P. J., J. WILLIAMSON, 10 (1984) 1082. — 3. DELEY, J., P. DENI-KAE, Drug-induced extrapyramidal syndromes. In: VINKEN, P. J., G.W. BRUYN (Eds): Handbook of Clinical Neurology. (North Holland, Am-sterdam, 1968). — 4. SUZUKI, T., H. MATSAZUKA, CNS Drugs, 16(2002) 165. — 5. BRAS, M., B. HUTINEC, D. DEGME^I], N. MANDI],R. PALI], L. KNEZEVI], S. FILIPOVI], Neurologia Croatica, 52 (2003)93. — 6. HALL, E. D., R. B. JACKSON, J. M. SWAIN, J. A. M. A., 161(1956) 214. — 7. KOSTI], S.V., Parkinsonova bolest i parkinsonizam.In: KOSTI], S.V. (Ed.): Parkinsonizam i lekovi. (Beograd, Tipografik,1998.) — 8. CARLSSON, A., M. LUNDQUIST, T. MAGNUSSON, Na-ture, 180 (1957) 1200. — 9. NEGROTTI, A., S. CALZETTI, Mov. Disord.,12 (1977) 107. — 10. ARMON, C., C. SHIN, P. MILLER, Neurology, 47(1996) 626. — 11. BATEMAN, D. N., W. M. DARLING, R. BOYS, M. D.RAWLINGS, Q. J. Med, 71 (1989) 307. — 12. CROWLEY, T. J., M. M.HOEH, C. D. RUTLEDGE, Arch. Gen. Psychiatry, 35 (1978) 97. — 13.JANKOVI], J., Parkinsonism plus syndromes and secondary parkinso-nian disorders. In: PAHN, S., C. D. MARSDEN, J. JANKOVIC, J. (Eds):A comprehensive review of movement disorders for the clinical practitio-ner. (Movement Disorders, Aspen, 1995). — 14. RAJPUT, A. H., B. ROD-ZILSKY, O. HORNYKIEWICZS, Arch. Neurol., 39 (1982) 644. — 15.WSZOLA, B. A., K. M. NEWELL, R. L. SPRAGUE, Exp. Clin. Psycho-pharmacol., 9 (2001) 285. — 16. ADLER, C. M., A. K. MALHOTRA, I.ELMAN, D. PICKAR, A. BRIER, A., Neuropsychopharmacology, 26 (2002)295. — 17. CHONG, S. A., R. MAHENDRAN, D. MACHIN, H. C. CHUA,G. PARKER, J. KANE, J. Clin. Psychopharmacol., 22 (2002) 26. — 18.CAROFF, S. N., S. C. MANN, E. C. CAMPBELL, K. A. SULLIVAN, J.Clin. Psychiatry, 63 (2002) 12. — 19. CONNOR, D. F., K. E. FLETCHER,J. S. Wood, J. Clin. Psychiatry, 62 (2001) 967. — 20. LLORCA, P. M., I.CHEREAU, F. J. BAYLE, C. LANCON, Eur. Psychiatry, 17 (2002) 129.— 21. GIL-AD, I., B. SHTAIF, R. SHILOH, A. WEIZMAN, Cell. Mol.Neurobiol., 21 (2001) 705. — 22. SEGMAN, R.H., U. HERESCO-LEVY,A. YAKIR, T. GOLSTER, R. STROUS, D. A. GREENBERG, B. LERER,Biol. Psychiatry., 51 (2002) 261. — 23. LERER, B., R. H. SEGMAN, H.FANGERAU, A. K. DALY, V. S. BASILE, R. CAVALLARO, H. N. ASCH-AUER, R. G. MCCREADIE, S. OHLRAUN, N. FERRIER, M. MASEL-LIS, M. VERGA, J. SCHARFETTER, M. RIETSCHEL, R. LOVLIE, U.H. LEVY, H. Y. MELTZER, J. L. KENNEDY, V. M. STEEN, F. MAC-CIARDI, F., Neuropsychopharmacology, 27 (2002) 105 — 24. UZUN, O.,A, CANSEVER, A. OZSAHIN, Int. Clin. Psychopharmacol., 16 (2001)369. — 25. FUKUSAWA, T., M. TAKAHASHI, K. OTANI, K., Porg. Neu-ropsychopharmacol. Biol. Psychiatry, 25 (2001) 1477. — 26. TURRONE,P., G. REMINGTON, J. N. NOBREGA, Neurosci. Biobehav. Rev., 26(2002) 361. — 27. CAROFF, S. N., E. C. CAMPBELL, J. HAVEY, K. A.SULLIVAN, S. C. MANN, R. GALLOP, J. Clin. Psychiatry, 62 (2001)772. — 28. NEWELL, K. M., Y. G. KO, R. L. SPRAGUE, S. L. MAHOR-NEY, J. W. BODFISH, Am. J. Ment. Retard., 107 (2002) 270. — 29. FAB-BRINI, G., P. BARBANTI, C. AURILIA, Int. J. Geriatr. Psychiatry, 16(2001) 19. — 30. COSTA E SILVA, J. A., N. ALVAREZ, G. MAZZOTI, W.F. GATTAZ, J. OSPINA, V. LARACH, S. STARKSTEIN, D. OLIVA, L.COUSINS, M. TOHEN, C. C. TAYLOR, J. WANG, P. V. TRAN, J. Clin.Psychopharmacol., 21 (2001) 375.S. Tomi}Department of Neurology, University Hospital Osijek, J. Huttlera 4, 31000 Osijek, Croatiae-mail: s.filipovic@vip.hrPRIKAZ PACIJENATA: JATROGENI EKSTRAPIRAMIDNI SINDROMS A @ E T A KCilj rada bio je prikazati bolesnike lije~ene od jatrogenog ekstrapiramidnog sindroma (D-IMD) na Klinici za neuro-logiju Klini~ke bolnice Osijek. Prikazali smo bolesnike lije~ene u periodu od 10 godina (od 1992–2002. god.). U ana-liziranoj skupini je bilo 14 bolesnika. Razlozi za hospitalizaciju bili su u 6 bolesnika smetnje gutanja, u 3 bolesnikaneurolepti~ki maligni sindrom (NMS), 2 bolesnika su bila hospitalizirana zbog mo`danog udara, 2 bolesnika imala sugu{enje bolusom hrane i u 1 bolesnika su bile prisutne smetnje govora. Radna dijagnoza za ve}inu pacijenata bila jeneurolo{ka bolest, tek je kasnije postavljena dijagnoza D-IMD, isklju~enjem primarne neurolo{ke bolesti ili kao pri-dru`eni poreme}aj osnovnoj neurolo{koj bolesti. Devet pacijenata dijagnosticirano je kao Parkinsonov sindrom, 3 kaoNMS, a 4 kao orolingvalne diskinezije samostalno ili u kombinaciji sa Parkinsonovim sindromom. D-IMD je naj~e{}euzrokovan neurolepticima. Time obja{njavamo mali broj hospitaliziranih bolesnika zbog ovog sindroma na Klinici zaneurologiju.S. Butkovi}-Soldo et al.: Drug-Induced Movement Disorders, Coll. Antropol. 29 (2005) 2: 579–582582

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