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Tardive DyskinesiaDiagnostic Issues,Subsyndromes, and C onc urren t M ovementDisorders: A Study of State HospitalInpatients Referred to a Movement DisorderConsultation Serviceby Edward C . Lauterbach, W . Qrady Carter, Kevin M . Rathke,Brian H . Thomas, Samuel D . ShiUcutt, Robert L. Vogel, Norman C. Moore,James W . Mimbs, and WU liam H. Nelson

AbstractOf 49 state hospital patients referred for movementdisorder consultation for tardive dyskinesia (TD), 11(23.9%) of 46 meeting inclusion criteria had move-ment disorders other than TD. These other disordersled to a false diagnosis of TD in 6 subjects (12.2%).Between-day dyskinesia variability affected TDascertainment in only 3.2 percent of subjects.Prevalences of other neurological conditions in the30 patients identified with definite TD were parkin-sonism (90%), dystonia (25%), akathisia (16%),cerebellar signs (40%), dysmetria (23%), cerebellartremor (17%), tardive dystonia (3.3%), and tardiveakathisia (33 % ). Concurrence rates of parkinsonismwith TD varied significantly according to which clin-ical signs were used to define parkinsonism. Using arating score threshold of at least mild, rigidityoccurred in 793 percent, bradykinesia in 55.2 per-cent, and resting tremor in 41.4 percent of subjectswith TD; more significant rigidity occurred in 41.4percent, bradykinesia in 31.0 percent, and restingtremor in 20.7 percent Concurrence rates of neuro-logical conditions with TD subsyndromes were dis-tributed rather evenly according to condition preva-lences, except for an association of cervicotruncalTD with bradykinesia (perhaps because of ventrome-dial striatal presynaptic and postsynaptlc D2 block-ade, respectively). These findings, as well as theoccurrence of equal gender ratio and relative under-representation of bipolar and alcohol disorders insubjects with definite TD, are discussed.

Keywords: Tardive dyskinesia, parkinsonism, dys-tonia, akathisia, cerebellar signs, tremor.Schizophrenia Bulletin, 27(4):601-614,2001.

Tardive dyskinesia (TD) has been a major concern inpatients receiving antipsych otics. This is especially true instate hospitals, where many patients have psychotic disor-ders or psychotic manifestations requiring long intervalsof t reatment wi th an t ipsychot ics . Whi le TD may bebecoming less of a risk with the advent of atypicalantipsychotics, it is still of concern. M oreover, as the inci-dence of TD declines in the context of these newer drugs,the differential diagnosis of these movements becomesever more important in correctly determining movementdisorder etiology. Some of these etiologies have importantneuropsychiatric morbidities (e.g., Huntington's disease).

Although TD ha s been extensively studied, the presentstudy offers a unique perspective and reports findings froma diagnostic consultation service. There are few studies inthe literature that examine TD from the vantage point of amovement disorder consultation service. We are not aw areof any consultation service studies that simultaneously andsystematically determine alternative movement disorderdiagnoses, distinct anatomical TD subsyndromes, specificfeatures of parkinsonism, comprehensive concurrence ratesof various movement disorders and cerebellar signs, andclinical correlates of both TD subsyndrome s and movementdisorders, including negative and positive symptoms ofschizophrenia. Yet such information could enhance diag-nostic assessment and im prove our understanding of TD .The authors were asked to provide diagnostic consul-tation for patients with suspected TD. Because dyskinesiavariability (Kane et al. 1992) and alternative diagnosesthat simulate TD complicate diagnostic assessment, studyof the clinical impact of these confounding factors upon

Send reprint requests to Dr. E. Lauterbach, Mercer University Schoolof Medicine, Dept of Psychiatry and Behavioral Sciences, 655 First St.,Macon, GA 31207; e-mail: [email protected].

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TD diagnosis was undertaken. The concurrence rates ofother extrapyramidal syndromes and cerebellar signs withTD anatomical subsyndromes as well as the clinical corre-lates of these TD subsyndrbmes were also determined.Beyon d its clinical utilities, identifying associations of TDwith other motor signs may reveal additional clues toneural circuit pathophysiologies in TD .We therefore assessed the following hypotheses: (1)between-day variability in TD significantly reduces clini-cal ascertainment when patients are evaluated for TD on 2different days; (2) detailed clinical assessment usingblinded examination and blinded chart review for alterna-tive etiologies of movement disorders leads to a diagnosisother than TD in a significant nu mber of cases; (3) the fre-quencies of association between various parkinsoniansigns (e.g., rigidity and tremor) with TD differ signifi-cantly; and (4) various TD subsyndromes are associatedwith specific patterns of concurrent neurological condi-tions (i.e., parkinsonian rigidity, bradykinesia, tremor, dys-tonia, akatbisia, terminal kinetic tremor, and dysmetria).

MethodsOne of us (S .D.S. ) reviewed Abnormal InvoluntaryM o v e m e n t s S c a l e ( A I M S , A m e r i c a n P s y c h i a t r icAssociation 1992) scores for the presence and severity ofabnormal movements in 620 randomly selected patients ata 1,320-bed state hospital facility in Georgia. Hospitalpolicy required annual AIMS assessments on all patients.Each chart was also reviewed for neuroleptic exposureand documentation of continued presence of abnormalmovements. Fif ty-four patients from an adult chronicinpatient ward were consecutively referred for consulta-tion based on total ATMS scores of 2 or greater on anysingle movement item. Forty-nine of these patients agreedto par t ic ipa te in the s tudy and gave s igned wr i t teninformed consent. Two of us (K.M.R. and E.C.L.) thenexamined these 49 patients with suspected TD to deter-mine whether the movements actually represented TD.Sample Description. The mean age for the 49 subjectswas 64.18 13.39 years, and there were 27 women and 22men. All 49 subjects were right-handed. AIMS total scoresaveraged 15.49 5.34. Duration of movements (ascer-tained from the chart review) averaged a mean of 63.14 86.22 months (range 1-452 months). Six subjects hadmov ements for less than 1 year, whereas 43 had mo ve-men ts for longer than 1 year. No su bject had been exposedto atypical antipsychotics. Mean duration of neurolepticexposure (ascertained from the chart review) was 21000 141.25 months, with a range of 0-5 18 mon ths. Although allsubjects had been exposed to neuroleptics, 11 were off neu-roleptics when evaluated and 3 had not been on neurolep-

tics while in the hospital, as determined from the chartreview. DSM-III-R (American Psychiatric Association1987) chart diagnoses for the 49 subjects included chronicundifferentiated schizophrenia (n = 17), chronic paranoidschizophrenia (n = 5), catatonic schizophrenia (n = 3),residual schizoph renia (n = 2), schizoaffective disorder (n =1), delusional disorder (n = 1), bipolar disorder (ji = 5), andorganic mood disorder (n = 1). Other diagnoses sometimesoverlapping with psychotic and mood disorders includedprimary degenerative dementia (n = 13), mental retardation(n = 11), alcohol abuse (n = 6), and anxiety disorders nototherw ise specified (n = 2).Protocol. Two trained raters (K.M.R. and E.C.L.; interrateragreement 94%) separately determined the presence ofdyskinesia in all 49 patients on 2 different days that were1-3 days apart during the same week. Raters were blind tochart information, knowing only that the patient wasreferred for evaluation of possible TD. The protocolincluded a clinical neurological exam, a clinical movementdisorder exam, and rating of movements on scales includ-ing the AIMS, the Unified Parkinson Disease Rating Scale(UPDRS, Hoehn and Yahr 1967), the Dystonia MovementScale (DMS, Burke et al. 1985), the akathisia scale (Brownet al. 1987), and the Brief Psychiatric Rating Scale (BPRS,Overall and Gorham 1988).

After examinations on all patients had been com-pleted, each subject's chart was then comprehensivelyreviewed with regard to admission evaluations, dischargesummaries, consultation notes, laboratory studies, andmedication records. Chart review was undertaken by aninvestigator (W.G.C.) blind to the findings of the exami-nation protocol. Detailed scrutiny of the charts wasemployed; the investigator looked for medical conditionsother than TD that are associated with movement disor-ders (Hyde et al. 1991; American Psychiatric Association1992; Rodnitzky and Keyser 1992). Data from examina-tion and chart review were then integrated (E.C.L. andW.G.C.) to determine the final diagnosis of TD. Featuresdistinguishing TD from other movement disorders havebeen discussed elsewhere (Hyde et al. 1991; Rodnitzkyand Keyser 1992).

The chart-blind examination protocol was sequencedas indicated above because the authors anticipated thatsome patients would become tired during the lengthyexamination period (60-120 minutes). The benefit of thisis that fatigue can sometimes elucidate movement disor-ders that otherwise would not be apparent The disadvan-tage of fatigue is failure to complete all study items.Consequently, we structured the protocol so that move-ment disorders would be evaluated first, followed by psy-chiatric items. Completion rates for each protocol itemwere as follows: neurological exam, 94% (n = 46); move-ment disorder exam, 96% (n = 47); AIMS, 94 % (n = 46);

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UPDRS, 96% in = 47); DMS, 76% (n = 37); akathisiascale, 63% (n = 31); and BPRS, 29% (n = 14). Usingthese data, the authors considered the following: (1) thevariable presence of dyskinesia on different days; (2) thereliability of the diagnosis of presumed TD prior to refer-ral; (3) the form of the movements, TD anatomic distribu-tion, and concurrence rates of other movement and neuro-logical disorders with TD; and (4) the clinical correlatesof certain movement disorder syndromes, including nega-tive symptoms of schizophrenia.Definitions and Diagnosis of TD. Definite TD was diag-nosed if the patient showed movements consistent withTD to both examiners, if chart review did not evidenceany alternative etiologies, and if the movements met thecriteria of Schooler and Kane (1982). Additionally, thepresence of choreoathetoid movements was required todetermine a diagnosis of definite TD, in contrast to othertardive diagnoses such as tardive dystonia (requiring dys-t o n i c m o v em en t s ) an d t a rd i v e ak a t h i s i a ( r eq u i r i n gakathisic movements). Withdrawal TD was excluded byreview of medication records. Presumptive TD was diag-nosed i f TD movements were apparent to one ra ter(K.M.R.) but not the other and chart review findings wereco m p a t i b l e w i t h TD. Possible TD was d iagnosed i fchoreoatheto id movements cons i s ten t wi th TD wereobserved by both raters and chart review findings werecompatible with TD but other causes of dyskinesia couldnot be definitively excluded. Questionable TD was diag-nosed if movements were not seen by either examiner butTD-like movements previously had been documented inthe chart.Variability of Dyskinesia on Different Days.Agreement between the two raters on 2 different days asto the presence or absence of movements resembling TDfor the 49 subjects was determined. The authors computedthe rate of agreement for subjects with presumptive TD.Reliability of the Diagnosis of TD Prior to Referral.The authors determined movement disorder diagnoses forthe 49 subjects using evidence of medical and neurologi-cal disease taken from the chart (admission assessments,discharge summaries, consultant notes, laboratory studies,medications other than neuroleptics, etc.) and the neuro-logical and movement disorder examinations. This infor-mation was integrated to verify the presence or absence ofdefinite TD.Movement Form, TD Anatomic Distr ibution , andMovement Disorder Prevalence and ConcurrenceR ate s . Movements were inspected for ev idence ofchorea , a thetos i s , park insonism, dys tonia , akath i s ia ,t r em o r , m y o c l o n u s , an d o t h e r m o v em en t d i s o rd e r s .

Prevalences were determined. The authors assessed theanatomic distribution of TD and the frequency of associa-tion of other movements in subjects with definite TD.Concurrence rates between TD anatomical subsyn-dromesorobuccofaciolingual (OBFL), upper extremity,lower extremity, and cervicotruncaland extrapyramidalsyndromes (parkinsonism, dystonia, and akathisia) andcerebellar signs (terminal kinetic tremor and dysmetria;no subjects had ataxia or dysdiadochokinesia) were deter-mined. Because parkinsonism can be defined in variousways (by degree of symptom severity and by number ofcardinal features), the authors determined neurologicalconcurrence rates for subjects with at least mild features(UPDRS item score > 0) and for those with more severefeatures that were definitely present without activationprocedures (UPDRS item score > 1). Concurrence rateswere determined for these different severity levels ofrigidity, bradykinesia, and resting tremor. In summary, weevaluated concurrence rates of each neurological condi-tion with each T D subsyndrome.Hypothesis Testing. Hypothesis 1 was evaluated bycomparing me rate of cases of definite TD determined bythe two raters on 2 different days to the rate of cases ofdefinite TD determined by the single rater on a single day.Hypothesis 2 was tested by comparing the rate of definiteTD cases in the original sample of 49 subjects referred forconsultation to the rate of definite TD cases in the 30 sub-jects completing consultation. Hypothesis 3 was evaluatedby comparing the concurrence rates of parkinsonismrigidity with parkinsonian resting tremor among subjectswith definite TD. McNemar's test (Fleiss 1981) was usedto evaluate hypotheses 1, 2, and 3 because data werepaired (95% confidence intervals are presented to assessdifferences in evaluations). The alpha level was adjustedfrom 0.05 to 0.0167 as appropriate for the three hypothe-ses assessed using this statistical test. Hypothesis 4 wasassessed by means of odds ratios. Odds ratios with 95 per-cent confidence intervals were determined for associationsin which the frequency of the neurological condition in aparticular TD subsyndrome varied by at least 20 percentfrom the frequency of the neurological condition in theoveral l sample of subjects with defini te TD. Becausesome cell sizes were less than five, odds ratios were thentested for significance using Fisher's exact test. The alphalevel was adjusted from 0.05 to 0.0167 as appropriate fordie three odds ratios assessed using this statistical test

ResultsVariability of Dyskinesia on Different Da ys (Hypothesis1) . Between-day variability in TD did no t significantlyreduce clinical ascertainment when patients were evaluated

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for TD on 2 different days (30/31 vs. 31/31; McNemar ' stest x 2 = 0.0, df = 1, p = 1.00; 95% confidence interval forthe difference between evaluations was [-0.031, 0.095]).The two raters agreed on the presence of movements con-sistent with TD in all but one subject (30 of 31 , 96.8%). Inthis single unconfirmed case, movements suggestive of TDwere seen by only one examiner.Reliabil ity of the Diagnosis of TD Prior to Referral(Hyp oth e s i s 2 ) . Detai led c l in ical assessment us ingblinded examination and blinded chart review for alterna-tive etiologies of movement disorders led to a diagnosisother than TD in a significant number of cases (30/49 vs.30/30; McNemar's test x 2 = 17.05, df = 1, p = 0.00004;95% confidence interval for the difference in diagnosiswas [0.252, 0.524]).

Integrating the blinded chart and examination data,the authors determined movement disorder diagnoses forthe 49 subjects as detailed in table 1. Among the 30 sub-jects with confirmed TD, the mean age was 62.43 14.60years , and there were 15 wom en and 15 men. AIMSscores averaged 16 .59 4 .69 . The mean durat ion ofmovements was 56 .87 80 .82 months ( range 5-248months) . Mean durat ion of neuro lept ic exposure was224.60 130.42 months (range 18-518 months). Threesubjects had been o n neuroleptics for less than 1 year.Seven were off antipsychotics when evaluated, but all had

been on neuroleptics previously. Chart diagnoses for the30 subjects included 24 with schizophrenia (14 chronicundifferentiated type, 5 chronic paranoid type, 3 catatonictype, 2 residual type) and 1 with delusional disorder.Other diagnoses sometimes overlapping with psychotican d m o o d d i s o rd e r s i n c l u d ed p r i m ary d eg en era t i v edementia (5), mental retardation (7), and alcohol abuse(1). No subject carried a diagnosis of organic mood disor-der, schizoaffective disorder, bipolar disorder, or anxietydisorders, in contrast to the original sam ple of 49 subjects.There were no significant differences between these 30subjects and the original 49 subjects for any of the abovevariables (i .e. , age, AIMS scores, movement durat ion,neuroleptic exposure, current administration of antipsy-chotics, or diagnoses) except for nonsignificant trendstoward less bipolar disorder (p = 0.08) and alcohol abuse(p = 0.05) in subjects with TD (Fisher ' s exact test) .However, among the 30 subjects with TD, men wereyounger than women (age 56.73 13.40 vs. 68.13 13.88 years, t = -2 .289 , df = 28, p = 0.03) and tended tohave a shorter course of TD (20.43 23.87 vs. 51.67 63.88 months, Mann W hitney U = 63.0, p = 0.066).Movem ent Form, TD Anato mic Distr ibution , andMovement Disorder Prevalence and ConcurrenceRates (Hypotheses 3 and 4). The frequencies of associa-tion between various parkinsonian signs with TD differed

Table 1 . Movem ent disorder diagnoses In the 49 subjectsCondit ion Subjects (n)Original sampleSubjects refusing neurological examTD not confirmed by second examiner

Subjects eligible for diagnosis of TDDefinite T DSevereModerateMildMinimalPossible TD (confirmed by 2 e xaminers and chart review)Possible edentulous dyskinesiaPossible post-infarct dyskinesiaPossible post-t iead trauma or -hepatic dyskinesia

Questionable TD (not seen by either examiner but suggestedby chart do cumentation)Movem ent disorder other than TD (confirmed by 2 examinersand chart review)Huntington's diseaseHyperthyroid choreaAntjconvulsant-related choreaSenile dyskinesia

4921463002226

5221

2112

Atofe.TD = tardtve dyskinesia.

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significantly (23/29 vs. 12/29; McN emar's test x2 = 7.69,df= 1, p = 0.0055; 9 5% confidence interval for the differ-ence between r igidity and t r emor is [0 .215, 0 .543] ) .Various TD subsyndromes were not associated with spe-cific patterns of concurrent neurological conditions (theonly association found was bradykinesia with cervicotrun-ca lTD) .

Rating scale completion rates for the 30 subjects withdefinite TD were clinical neurological exam, 30 (100%);ATMS, 30 (100%); UPDRS, 29 (97%); DMS, 24 (80%);akathisia scale, 19 ( 63%) ; and B P R S , 10 ( 33%) . Theanatomic distribution of choreoathetoid dyskinesia in the30 subjects with definite TD and point prevalences areshown in table 2. OBFL dyskinesia was present in someform in nearly all subjects, with upper extremity involve-ment in two-thirds, lower extremity involvement in nearlyhalf, and axial (cervicotruncal) TD in about one-quarter

(exact percentages given in table 2). Among OBFL com-ponents, lingual dyskinesia occurred in most, perioral inhalf, mandibular in one-third, and facial in one-fifth of the30 subjects (exact percentages given in table 2). Therewere no signif icant differences in concur rence ra tesbetween the various TD subsyndromes.Disorders associated with TD (table 2), from mostcommon to least common, were parkinsonism, dystonia,cerebellar dysmetria, terminal kinetic tremor, akathisia,tardive akathisia , and tardive dystonia. Parkinsonismoccurred in most subjects, dystonia was infrequent (oftenoccurr ing with parkinsonism), and akathisia was rare.Among parkinsonian features, rigidity was most common,followed by bradykines ia , and then tremor ( table 2).Twenty-seven subjects with definite TD consented to theclinical evaluation of movement disorders other than TD,parkinsonism, dystonia, and akathisia . Of these, none

Table 2. Choreoathetoid TD syndrome s: Anatom ical distribution in 30 subjects with definite TDCondition Subjects1Tardive dyskinesia (n = 30 of 30 definite TD subjects assess ed)OrobuccofaciolingualFacialPerioralMandibularLingualUpper extremityLower extremity

CervicotruncalParkinsonism (n = 29 of 30 definite TD subjects assessed)Rigidity(UPDRS ratings > 0)(UPDRS ratings >1)Bradykinesia(UPDRS ratings > 0)(UPDRS ratings >1 )Resting tremor(UPDRS ratings > 0)(UPDRS ratings >1 )Rigidity + bradykinesia(UPDRS ratings > 0)(UPDRS ratings >1 )Rigidity + bradykinesia + tremor(UPDRS ratings > 0)(UPDRS ratings >1 )Dystonia (n = 24 of 30 definite TD subjects assessed)Akathisia (n = 19 of 30 definite TD subjects assessed)Cerebellar signs (n = 30 of 30 definite TD subjects assessed)DysmetriaTerminaJ kinetic tremor

30(100.0%)2961411252014726231216912614482631275

(96.7%)(20.7%)(48.3%)(37.9%)(86.2%)(66.7%)(46.7%)(23.3%)(89.7%)(79.3%)(41.4%)(55.2%)(31.0%)(41.4%)(20.7%)(48.3%)(13.8%)(27.6%)(6.9%)

(25.0%)(15.8%)(40.0%)(23.3%)(16.7%)

Note.TD = tardive dyskinesia; UPDRS = Unified Parkinson Disease Rating Scale.1 The numbers and percentages of patients with movement disorders and their subsyndromes. Percentages are proportions of the num-be r of subjects actually assesse d for each feature.

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manifested myoclonus or action-postural tremor. Tardivedystonia and tardive akathisia each occurred in one sub-ject, coexisting in the same patient. Other tardive phe-nomena reported in the literature (tardive parkinsonism,myoclonus, tremor, tic) were not apparent in this sample.Some of the seven subjects off antipsychotics had TD andparkinsonism, but n one had dystonia or akathisia.Concurrence rates of parkinsonism often varied by anorder of magnitude, depending upon how parkinsonismwas defined (table 2). In general, rigidity was most com-mon, followed by bradykinesia and then resting tremor.Except for bradykinesia, concurrence rates of neuro-logical features did not significantly differ between thevarious TD subsy ndrom es. Only three neurological condi-tions met the criterion for odds ratio examination of theirrelationship to TD subsyndromes. Each of these threeconditions varied by 20 percent from expected rates inonly one TD subsyndrome, cervicot runca l TD. Odds

ratios were determined for dystonia (odds ratio = 4.00,95% confidence interval 0.42-37.78, p = 0.25), bradyki-nesia > 1 (odds ratio = 11.2, 95% confidence interval1.6-80.3, p = 0.0164), and tremor > 0 (odds ratio = 0.17,95% confidence interval 0.017-1.62, p = 0.11). The asso-ciation of bradykinesia with cervicotruncal TD remainedsignificant after Bonferroni correction of the alpha level to0.0167.

DiscussionIn contrast to previous cross-sectional studies of state hos-pital patient populations, this study provides the perspec-tive of a movement disorder consultation service within astate hospital . Ascertainment methodology involved ablinded, lengthy, and comprehensive neuropsychiatr icassessment coupled with a blinded chart review. Interrateragreement was high. The findings of this study should beinte rpre ted in l ight of severa l considera t ions . F i r s t ,although a large number of studies have considered therelationship of other movement disorders to TD in a vari-ety of different patient populations and clinical settings,there appear to be no studies of patients selected for possi-ble TD from movement disorder consultation services inpsychiatric hospitals. Thus, the study appears to be uniqueand is not strictly comparable with the extant literature.Some studies have addressed movement disorder preva-lences in special populations incomparable to that of thepresent study, including children (Richardson et al. 1991),patients with particular diagnoses such as mental retarda-tion (Rao et al. 1987) or affective disorders (Ghadirian etal . 1996), patients on specific drugs (multiple studies),and normal community populations (Green et al. 1993).Second, patients were referred for evaluation of suspectedTD . This limits somewhat the generalizability of these

results to state hospital populations, because the study isnot strictly cross-sectional in nature. Third, most patientsin this study suffered mild dyskinesia, making the resultsmost relevant to patients with relatively less severe TD.Fourth, all 49 subjects were right-handed, perhaps point-ing to a somewhat atypical sample. There were, however,more women than men and the mean age of the subjectswas 64 years, consistent with findings in other studies ofTD (Casey 1990; Morgenstern and Glazer 1993). Theaverage duration of suspected TD was 5 years but variedconsiderably, consistent with what one might expect tofind in a state hospital population. Moreover, the durationof chronic neuroleptic exposure and the array and fre-quency of psychiatric diagnoses are also representative ofstate hospital populations. Thus, overall, the features ofthe sample are consistent with state hospital populations.Fifth, the examination procedure was rather long, whichenhanced our ability to identify movement disorders. Thisr igorous, blinded ascertainment methodology coupledwith blinded comprehensive chart reviews may reduce thecomparability of the findings to studies that employ only abrief ATMS exam. Indeed, previous work has demon-strated that methodological and observational rigor canmore than double ascertainment rates for TD and parkin-sonism (Hansen et al. 1992a). Finally, die lengthy proce-dure also reduced the sample sizes for some of the ratingscale assessments (dystonia and akathisia), because somepatients became tired by this point in the protocol. Thefindings must be viewed in light of the limited size of thesample and the special considerations enumerated above.Hypotheses . The findings of this study suggest thatbetween-day variability in TD has little impact in caseascertainment when patients are assessed in detailed fash-ion. Such evaluation, however, identifies a significantnumber of false positive TD cases, indicating the meritsof careful neurological exam ination and review of the pastmedical history and laboratory data. Concurrence rates forparkinsonism in TD can vary signif icantly dependingupon what clinical signs are used to ascertain cases. Ratesof concurrent neurological conditions with various TDsubsyndromes appear to reflect their underlying preva-lence, with the exception of an apparent associationbetween cervicotruncal TD and bradykinesia. Thus, mostconcurrence rates appear to represent true comorbidityrates (i.e., rates between independent disorders). A ttentionto these details, apparent only on careful clinical assess-ment, can inf luence clinical diagnosis as well as ourunderstanding of the nature of TD.Variability of Dyskinesia on Different Days. Rateragreement was 96.8 percent as to presence of TD. Thissuggests rel iable ascertainment of TD and clinically

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insignificant between-day variability in this study. Thislack of clinically significant v ariability co ntrasts w ith pre-vious studies documenting significant intrapatient vari-ability in TD movements assessed clinically (Richardsonet al. 1982) and instrumentally (Stanilla et al. 1996; Baca-Garc ia et al . 1999 ). The study by Richard son et al .employed 8-minute frequency counts over 11 weeks insix patients and found the degree of variability significantenough to lead to a false negative diagnosis of TD.Bergen et al. (1984), however, found within-rater vari-ability to dominate within-patient variability in clinicallyassessed TD. Instrumentally assessed TD studies indicatethat diurnal fluctuation (Stanilla et al.), time since wak-ing, TD severity, and smoking (Baca-Garcia) contributeto within-patient variability. In addition, factors otherthan natural fluctuations in dyskinesia could have oper-ated in the present study to produce TD variabil i ty.Although not apparent to the initial rater who was presentat both ratings, it is possible that subtle changes in psy-chiatric or medication status may have occurred betweenratings. However, such changes between ratings wouldonly serve to increase the variability of TD, making iteven more difficult to achieve good interrater agreement.The potential operation of these factors only adds cre-dence to the conclusion that between-day TD variabilitydoes not significantly reduce clinical ascertainment whenpatients are evaluated for TD on 2 different days. Theduration of the examination in the present study allowedprotracted assessment and patient fat igue, improvingascertainment reliability. This also occasionally led toobserving movements not otherwise apparent. For exam-ple, one patient manifested dystonia only after 30 minutesof examination. Careful clinical assessment in this man-ner may contribute to the observation of minimal vari-ability, contrasting with findings using more sensitiveinstrumental methods and shorter periods of assessment.Reliability of the Diagnosis of TD Prior to Referral.Chart-blind examination and examination-blind chartreview reduced the chances for potential bias in assessingmovement disorders and chart data. Although chart diag-noses of TD can be notoriously unreliable (as demon-strated in table 1), we did not use chart data in this way.Rather, we used the chart to search for data supportive ofmovement disorder diagnoses other than TD. In this way,chart review improved the accuracy and specificity of TDdiagnosis, although the duration of movements may havepredated their documentation in the chart. Final integra-tion of chart data with examination data can enhancediagnostic validity and reliabil i ty. Five subjects hadmovements that may have represented either TD or othercondi t ion s (Hyde e t a l . 1991; Amer ican Psychia t r icAssociation 1992; Rodnitzky and Keyser 1992), includ-ing previous stroke, head trauma, non-Wilsonian hepatic

cirrhosis, and edentulous dyskinesia (table 1). These find-ings highlight the need for careful vigilance about neu-ropsychiatric disorders that can lead to a false positivediagnosis of TD. Another six subjects had movement dis-orders other than TD, including Huntington's disease,hyperthyroid chorea, anticonvulsant-related chorea, andsenile dyskinesia (table 1). Dys kinesias other than TDoccurred in more than 20 percent of the sample, indicatingthat alternative attributions for dyskinesias besides TDshould be considered in clinical populations, especially insubjects with mild TD as in the present sample. In addi-tion to leading to proper diagnosis, exploration of alterna-tive etiologies can lead to the elucidation of other condi-tions such as Huntington's disease and hyperthyroidism,which carry their own psychiatric morbidities.Sa m ple Co m pa ra bi l i t y : E qua l Gender Ra t io a ndRelative Absence of Bipolar and Alcohol Disorders inDefinite TD. Comparing the sample of 30 subjects withdefinite TD to the other 19 subjects of the original sampleof 49, the equal number of males and females and the rel-ative absence of bipolar and alcohol diagnoses among the30 subjects with definite TD is striking. The equal sexratio may relate to methodological differences (e.g., refer-ral to study, ascertainment rigor, etc.) between this studyand those employed in TD risk factor studies (Casey1990). Referral bias in favor of males is possible becausethe only gender differences in definite TD were signifi-cantly young er age and a non significant trend towardshorter TD duration in males. Nevertheless, females pre-dominated in the original sample of 49 subjects, and ear-lier findings of female gender as a risk factor for TD mayin part reflect inadequate exclusion of other movementdisorders. Equal gender ratios and younger age and lessneuroleptic exposure in patients with definite TD are con-sistent with previous findings. Studies of risk factors forTD in long-term outpatients (Morgenstern and Glazer1993) and patients with minimal neuroleptic exposure(Harris et al. 1992) as well as a review of the African andAsian literature (Pandurangi and Aderibigbe 1995) havealso found no significant effect of gender. Moreover, otherstudies in outpatients (Morgenstem et al. 1987; Joseph1990), younger patients (van Os et al. 1999), and patientswith minimal neuroleptic exposure (van Os et al. 1997)demonstrated that male gender rather than female genderwas associated with TD. Female gender has actually beenassociated with less risk for TD in patients with minimalneuroleptic exposure (van Os et al. 1997). Subject ageseems to affect gender-related risk for TD. In one study,TD severity was related to age in women but not in men(Moore et al. 1983), whereas in another study of subjectswith TD aged 40 or younger, younger men were at risk forTD but women were not (Woemer et al. 1991). Thus, thefindings of equal gender ratio and younger age and less

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neuroleptic exposure in men with TD are consistent withprevious findings in the literature, suggesting that youngermen may be at particular risk for TD .Affective disorders have been considered to representa risk factor for TD (Rush et al. 1982; Wolf et al. 1987;Casey 1988; Kane et al. 1988; O'Hara et al. 1993; Kane1999) and the absence of definite TD in the five subjectswith bipolar disorders from the original 49 subjects istherefore surprising. The absence of bipolar disorders insubjects with TD may in part reflect multiple dyskineto-genic conditions in some subjects and TD variability inothers: two subjects had "po ssible TD " (i.e., "definite TD "could not be diagnosed because the movements may haverepresented edentulous dyskinesia in one subject andpoststroke dyskinesia in the other); one subject had "ques-tionable TD" (not seen by either examiner but suggestedby chart documentation); and two had no evidence of TD(other than referral to the study). It is possible that the two

without evidence of TD may have had mood-dependentdyskinesias (Coleman 1989; Sandyk 1990) that were inremission at the time of the evaluation.Similarly, the relative absence of alcohol disordersamong subjects with definite TD is surprising, becausealcohol disorders are also considered a risk factor for TD(Olivera et al. 1990; Dixon et al. 1992; Duke et al. 1994;Jeste et al. 1995; Paulsen et al. 1996; van Os et al. 1997).An alcohol disorder was documented in only one subjectwith TD (3.3%) in contrast to 12.25 percent of the initial49 dyskinetic subjects, suggesting that careful screeningof patients with alcohol diagnoses may elucidate sourcesof dyskinesia other than TD. O'Hara et al. (1993) actually

found that recent use of alcohol was associated with lowerAIMS total scores. One study found that alcoholism pre-dicted TD in male patients with affective disorders (Wolfet al. 1987). Perhaps the absence of bipolar disorders insubjects with TD drove down the frequency of alcoholdisorders in these subjects. Alternatively, rigorous exclu-sion of other movement disorders may contribute to theequal gende r ratio and absence of bipolar and alcohol dis-orders in this study.TD Anatomic Distribution. TD more commonlyaffected superolateral aspects of the body than inferoaxialaspects (table 2), consistent with previous observations inthe l i terature (M cCre adie et al . 1982; Altamura et al .1990; Paulsen et al. 1996). Overall, the most frequentmanifestations of TD were lingual and finger dyskinesia.Neurological Condition Prevalence and ConcurrenceRates . Myoclonus, tic, action-postural tremor, tardiveparkinsonism, and tardive tremor were not encountered.Rates of tremor and all three parkinsonian signs were sim-ilar to those of Myslobodsky et al. (1986) in 49 patients

with TD. Rates for bradykinesia with rigidity were sub-stantially higher, likely due to lack of inclusion of isolatedb r a d y k i n e s i a i n a s c e r t a i n i n g p a r k i n s o n i s m b yMyslobodsky et al.The authors are unaware of any studies that specifi-cally and comprehensively determined prevalences andrates of concurrent parkinsonism, dystonia, akathisia, andcerebellar signs in patients with TD . Previous studies haveexamined the occurrence of movement disorders amongsamples of psychia t r ic pat ien t s wi thout del iberate lyselecting for TD (Wolf et al. 1985; Grohmann et al. 1990;Hansen et al. 1992*; O'Hara et al. 1993; van Harten et al.1996; Muscettola et al. 1999). Some have evaluated spe-cial populations of patients (Toenniessen et al. 1985; Raoet al. 1987; McCreadie et al. 1992). Other prevalencestudies have looked at the sequelae of individual drugs.St i l l other s tudies have considered the prevalence ofmovement disorders in community samples not selected

for psychiatric disorders (Green et al. 1993). In the pres-ent study, drug-induced parkinsonism was quite common,followed by dystonia and akathisia, which is similar toresults seen in a sample of 1,107 psychiatric patients(Grohmann et al. 1990), despite methodological differ-ences. Consistent with the high prevalence of parkinson-ism in the present study, rates of TD and drug-inducedparkinsonism were nearly identical in two studies of psy-chiatric inpatients (Hansen et al. \992b; van Harten et al.1996); TD was significantly associated with drug-inducedparkinsonism in 141 psychiatric pat ients in day care(O'Hara et al. 1993) and 99 consecutive Department ofVeterans Affairs male patients (Wolf et al. 1985). Theprevalence of akathisia in the present study is similar tothat of 194 inpatients with chronic psychiatric illnesses,where TD was present in 39.7 percent and akathisiaoccurred in 9.3 percent (van Harten et al. 1996). Akathisiawas absent in patients with cervicotruncal TD in the pres-ent s tudy , cons i s ten t wi th l inkage of drug- inducedakathisia to choreoathetoid orofacial and limb dyskinesia(Barnes and Braude 1985). Thus, although the methodol-ogy of the extant literature is not strictly comparable, therelative frequencies of TD, parkinsonism, dystonia, andakathisia are s imilar to those observed in the presentstudy.

Concurrence rates of parkinsonism can vary by anorder of magnitude, depending upon how parkinsonism isdefined. Regardless, rigidity was most common, followedby bradykinesia and then tremor (table 2). Table 3 dis-plays concurrence rates of movement disorders in patientswith TD calculated from the reported l i terature. VanHarten et al. (1997) required at least mild tremor, rigidity,or bradykinesia; Hoffman et al. (1991) required at leastmild ratings on two cardinal symptoms or moderate onone symptom; McCreadie et al. (1982) and Andreassen et

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Table 3. Concu rrence rates (%) of movement disorders In TD , from the literatureStudies

Conditions (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13)TDwithP2TDwitt iP

3PwithTD2PwithTD3TDwithDDwithTDTDwithAAwithTD

90481001002510016100

17199.1276.528

4 641

4560

5732

88753757

6053

8057

9273 4.3 4.829 5.7

40Note.A. = akathisia; D = dystonia; P = parkinsonism; TD = tardive dyskinesia.1 Columns refer to the following studies: (1) current study in 30 patients with TD, age 62.4 14.6 yrs, 50% male; (2) va n Harten et al.(1997) in 77 patients wtth TD, age 53.1 16.7 yrs, 72.7% male; (3) McCreacfie et ai. (1982) In 26 patients with TD and schizophrenia liv-ing in Nithsdale; (4) Andreassen et al. (1997) in 51 Nithsdale patients with TD, age 57 16 yrs, duration of illness 25 16 yrs; (5)Myslobodsky et al. (1986) In 49 C aucasian chronic Inpattents with TD , mean age 6 2.5, 5 1 % male and 47% with organic brain disorder(6) CTH ara et al. (1993) In 16 long-term psyc hiatric patients with TD , age 48.7 1 4.4 yrs, 57.5% male; (7) Hoffm an et al . (1991) in 30patients with DSM-III-R schizophrenia, age older than 55, treated with neuroleptics for at least 10 yrs, without previous neurological dis-ease, Including severe head injury; (8) subsampte of 22 patients from (7); (9) subsample of (8) followed up 2-4 yrs later; (10) Gureje(1989) in 47 Nigerian psychiatric patients with TD showing the concurrence rates wtth tardive dystonia; (11) Raja & Azzonl (1996) in 42consecutive psychiatric Inpa tlents wtth TD, age 50.5 13.3 yrs, 40 % male ; (12) Yassa et a). (1992) In 35 elderly patients w ith TD follow edup 5 yrs after their first exposure to neuroleptics, showing the concurrence rate with tardive dystonia; (13) Ganesh et a l. (1989) in 5 men-tally retarded patients with chronic akathisia on neuroleptics for at least 3 yrs.2 Mild parkinsonism as criterion threshold for ascertaining cases.3 Moderate parkinsonism as criterion threshold for ascertaining cases.

al. (1997) required mild rat ings on a global scale ofparkinsonism; and Myslobodsky et al. (1986) determinedparkinsonism as either present or absent. Given these defi-nitions, the concurrence rates of TD with parkinsonismfound by van Harten et al., McCreadie et al., Andreassenet al., and Myslobodsky et al. are lower than those of thepresent s tudy, perhaps due to younger age in the vanHarten et al. study, outpatient status in the McCreadie etal. and Andreassen et al. studies, and lack of inclusion ofisolated bradykinesia in the Myslobodsky et al. study. Incontrast, the concurrence rates of TD with parkinsonismof O'Hara et al. (1993) are higher despite much youngerage. The concurrence rates of TD with parkinsonism ofHoffman et al. are also higher, perhap s due to mo re severeTD in their sample. Comparisons of concurrence rates ofparkinsonism with TD, dystonia with TD, and akathisiawith TD to those of the present study are not appropriatebecause our sample was selected for the presence of TD.Given the variance in prevalence of parkinsonism, whichdepends upon case ascertainment definitions, evaluationof a single sign should not be relied upon for ascertainingparkinsonism. The most val id ascertainment s trategyrequires vigilance for each of the cardinal parkinsoniansigns.

The co-occurrence of parkinsonism and TD is to beexpected because both occur with neuroleptic treatment.W h e r e a s p a r k i n s o n i s m h a s b e e n a s s o c i a t e d w i thdopaminergic insufficiency and chorea with dopaminer-

gic excess, the relation of dopamine to chorea actuallyappears to be more complex, because the dopamine ago-nist apomorphine decreases chorea in Huntington's dis-ease (Albanese et al. 1995). The presence of dystonia inpat ients with parkinsonism and choreoathetot ic move-ments (TD) is consistent with the ability of dystonia tooccur both in parkinsonian condit ions (e.g. , Segawa'ss y n d r o m e ) a n d in c h o r e i f o r m d i s o r d e r s ( e . g . ,Hu nt ing ton ' s d i sea se) . Akath i s ia has s imi lar ly beenobserved in pat ien t s wi th TD (Ganesh e t a l . 1989;Sachdev 1993a and 1993>) as well as in patients withparkinsonism (Cornelia and Goetz 1994) and dystonia(Sachdev 1993a and 1993&).

Several anatomic subsyndromes of TD have been dis-criminated (Glazer et al. 1988; Gureje 1988; Kane et al.1992; Paulsen et al. 1996; Muscettola et al. 1999). Wetherefore anticipated varying concurrence rates of neuro-logical conditions for distinct TD subsyndromes, in con-trast to the present findings in which the only associationappeared to be bradykinesia with cervicotruncal TD. It ispossible that the small sample size of this study obscuredadditional associations. Although other extrapyramidalsyndromes and cerebellar signs were rather evenly distrib-uted among TD anatomical subsyndromes according totheir prevalences, it remains possible that larger samplesmay identify select ive associat ions. Nevertheless, theeven distribution among syndromes was not anticipatedand, absent specific associations, suggests that different

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(rather than common) functionally segregated neural path-ways mediate the different movement disorders.IAssociations of Bradykinesia With Cervicotruncal TD.The association of bradykinesia with cervicotruncal TD isconsistent with other investigations finding a direct rela-t i o n s h i p b e t w e e n p a r k i n s o n i s m a n d TD s e v e r i t y(Muk herjee et al. 1982; O'Hara et al. 1993 ; Mu scettola etal. 1999). Gerlach (1977) and Sachdev et al. (1996) foundsimilar correlations between parkinsonism and limb trun-cal TD. In particular, Gerlach noted a quite strong rela-t ionship with bradykinesia, consistent with the presentf inding. However, other studies have found either aninverse relationship (Chouinard et al. 1979; Toenniessenet al. 1985; Kucharski et al. 1987; Gerlach 1988; Gerlachet al. 199 3; van H arten et al. 1997) or no relation ship(Cali giuri et al . 1991 ; Hans en et al . 19926) betwe enparkinsonism and TD . Consequently, the relation of TD to

parkinsonism may depend upon the anatomic region ofTD and the parkinsonian symptom specified. A relationbetween bradykinesia and TD may be based in ventrome-dial str iatal neurons, which have been l inked to bothbrady kinesia (Am alric et al. 1995; Jellinger 1999) and TD(Gerlach 1985). Blockade of D2 receptors in the ventro-medial str iatal terr i tory associated with bradykinesiawould dis inhibi t vent ra l tegmenta l dopamine re leasethrough presynaptic D2 blockade and would thus increased o p a m i n e r g i c s t i m u l a t i o n o f v e n t r o m e d i a l s t r i a t a ldopamine Dl receptors, thereby increasing cervical TD(Peacock et al. 1990; Trugman et al. 1994) in the contextof enhanced bradykinesia. This is consistent with the sug-ge s t i on t ha t D 2 b loc ka de m a y be r e qu i s i t e f o r T D(Peacock et al. 1990; Trugman et al. 1994). Such a mech-anism may explain why only bradykinesia was associatedwith TD in only this body region, and why different stud-ies observe contradictory relationships between parkin-sonism and TD .

ConclusionsAlthough the subjects in this study were referred to amovement disorder consultat ion service, some of thesefindings generalize to state hospital patients with mild tar-dive dyskinesia. The more rigorous the evaluation, thegreater the diagnostic certainty. It is important to excludeother causes of dyskinesia when diagnosing TD. Patientswith definite TD should be monitored for other extrapyra-midal syndromes, which are treatable conditions with theirown morbidities. Although rates of concurrence of TD sub-syndromes with other neurological disorders depend sub-stantially on how these other neurological disorders areclinically defined, bradykinesia may b e associated with cer-vicotruncal TD. Otherwise, these data seem to indicate a

relative independence of movement disorders in terms ofco-occurrence. Given the sample size of this study, furtherresearch is needed to replicate these findings.

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The AuthorsEdward C. Lauterbach, M.D., is Professor of Psychiatry,Neurology, and Radiology, Department of Psychiatry andBehavioral Medicine, Department of Internal Medicine(Neurology Sec t ion) and Depar tment of Radiology,Mercer University School of Medicine, Macon, GA. W.Grady Carter, M.D., is Assistant Professor, Department ofPsychiatry, Mercer University, Macon, GA. Kevin M.Rathke, M.D., is Associate Consultant, Department ofN e ur o logy , M a yo Cl in i c , Roc he s t e r , M N . Br i a n H .Thomas, M.D., is Fellow, Department of Psychiatry,Emory University, Decatur , GA. Samuel D. Shil lcutt ,Pharm.D., Ph.D., is Associate Professor of Psychiatry,Depar tment of Psychia t ry and Behaviora l Sc iences ,Mercer University School of Medicine, and Director ofResearch, Center for Clinical Studies, Central StateHospital, Milledgeville, GA. Robert L. Vogel, Ph.D., isP r of e s sor o f B ios t a t i s t i c s , D e pa r tm e nt o f Fa m i lyMedic ine and Depar tment of Communi ty Medic ine ,Mercer Univers i ty School of Medic ine . Norman C.Moore, M.D., is Professor of Psychiatry, Department ofPsychiatry and Behavioral Sciences, Mercer UniversitySchool of Medicine. James W. Mimbs, M.D., is Professorof Psychiatry, Department of Psychiatry and BehavioralSciences, Mercer University School of Medicine, andMedical Director , Central State Hospital . Will iam H.Nelson, M.D., is Chairman and Professor of Psychiatryand Behavioral Sciences, Department of Psychiatry andBe ha v ior a l Sc i e nc e s , M e r c e r U nive r s i t y Sc hoo l o fMedicine. All authors were affiliated with the Departmentof Psychiatry and Behavioral Sciences, Mercer UniversitySchool of Medicine, at the time the work was done.

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