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Tardive Syndromes

Tardive Syndromes

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Published by: Dan Sam on Aug 12, 2012
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Spectrum of tardive syndromes: clinical recognitionand management
Roongroj Bhidayasiri,
Suthida Boonyawairoj
Tardive syndrome (TS) refers to a group of delayed onsetdisorders characterised by abnormal movements andcaused by dopamine receptor blocking agents (DRBAs).Classical tardive dyskinesia is a specific type of oro-buccal-lingual dyskinesia. However, TS may exist in otherforms
for example, stereotypy, dystonia, andakathisia
and frequently occur in combination. Theonset typically is insidious and after reaching itsmaximum severity it often stabilises. Frequently reportedrisk factors are age, dose and duration of neurolepticexposure, the use of conventional DRBAs, andco-existing mood disorders. This review highlights thebroad spectrum of TS, not limited to classical tardivedyskinesia, as well as the clues for its recognition.Despite challenges in the treatment of TS, dictated bythe different phenomenology, severity of TS and theneed for ongoing neuroleptic treatment, the authorsprovide evidence based recommendations for patientmanagement, which is not restricted to only withdrawalof the offending neuroleptics or the selection of analternative medication, such as clozapine. In a minority ofcases with significant functional disability, symptomaticor suppressive treatments should be considered.Recently, there has been a resurgence of stereotacticpallidal surgery for the treatment of TS. Although theefficacy of both pallidotomy and pallidal deep brainstimulation in dystonia has been encouraging, theevidence is still limited.
of tardive dyskinesia (TD) occurredmore than
ve decades ago, about 5 years after theintroduction of neuroleptic drugs into psychiatry.The original description of persistent abnormalinvoluntary movements induced by neurolepticagents was published in a paper by Schonecker in1957.
Since then, the phenomenon of TD alertedphysicians and the public to its iatrogenicity and toits medicolegal impact, further enhancing clinicalawareness of a potential negative and delayedimpact of these useful drugs on the nervous system. While tardive syndromes (TS) encompass allaspects of abnormal movements, tardive dyskinesia(TD) speci
cally refers to classical oro-buccal-lingual dyskinesia associated with
piano playing
nger movements. The involuntary movements of various phenomenology associated with neuro-leptic agents are classi
ed as TS, including classicoro-buccal-lingual dyskinesia, stereotypy, dystonia,akathisia, tics, myoclonus, tremor, and parkin-sonism. TS is now accepted as a separate andunique entity as a result of the principal adverseeffect of long term treatment with conventionalantipsychotic agents. In this review, we discuss theclinical issues related to TS, including clinicalrecognition of various phenomenologies of TS, notlimited to TD, and the practical management of this condition. Basic common principles of management of TS are also provided. Whenpossible, preventive measures should be consideredsuch as avoiding the use of neuroleptics whenalternative treatments are available, limiting thecourse of neuroleptic treatment, and carefullwatching for the earliest signs of TS. Once TS hasdeveloped, therapeutic choices often include thediscontinuation of neuroleptics in patients with TS(if possible), and a determination of which medi-cations may be considered for suppressing TS. Inmedically intractable cases, severe disability may force the need for chemodenervation or surgicalintervention.
TD refers to a group of disorders characterised by predominantly late onset and sometimes persistentinvoluntary movements (or a sensation of rest-lessness), which are caused by exposure to dopa-mine receptor blocking agents (DRBAs). The
rstinternational congress of movement disordersde
ned TD as a hyperkinetic movement thatdevelops during treatment with neuroleptics orwithin 6 months of stopping the offending agent,and it must persist for at least 1 month afterdiscontinuing all neuroleptics. A somewhatdifferent de
nition by the American PsychiatricTask Force requires 3 months of exposure toa DRBA for diagnosis of TD.
2 3
Diagnostic andStatistical Manual of Mental Disorders
, 4th edition(DSM-IV) criteria speci
es the shortest duration of exposure to DRBAs of at least 1 month in indi-viduals
60 years. The French term
is usedto denote its late onset during the course of neuroleptic therapy, and
refers tounnatural movements which may or may not beinvoluntary. Generally, TD does not appear untilafter 1 or 2 years of continued neuroleptic treat-ment, and almost never before 3 months. Becausevirtually all types of movement disorders have beenassociated with neuroleptic therapy, and this iden-tical clinical syndrome can be induced by otheragents in addition to neuroleptics (box 1), the term
tardive dyskinesia
is confusing and problematic.Traditionally and historically, the term
was used to describe a speci
c type of movement, characterised by oro-buccal-lingualdyskinesias.
There are several phenomenologicaldistinct types of abnormal movements and they areclassi
ed into classical tardive dyskinesia, tardivestereotypy, tardive dystonia, tardive akathisia,tardive tremor, tardive myoclonus, and tardivetourettism (box 2).
It remains unclear if tardive
Chulalongkorn ComprehensiveMovement Disorders Center,Department of Medicine,Faculty of Medicine,Chulalongkorn University andKing Chulalongkorn MemorialHospital, Thai Red CrossSociety, Bangkok, Thailand
Department of Neurology,David Geffen School of Medicineat UCLA, Los Angeles,California, USA
Correspondence to
Roongroj Bhidayasiri,Chulalongkorn ComprehensiveMovement Disorders Center,Division of Neurology,Chulalongkorn UniversityHospital, Bangkok 10330,Thailand; rbh1@ucla.eduReceived 13 May 2010Accepted 26 October 2010Published Online First3 December 2010132
Postgrad Med J
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parkinsonism truly exists. The term
classical tardive dyskinesia
will be used in this review to denote a characteristic oro-buccal-lingual dyskinesia. Although detailed and somewhat impractical,this differentiation into speci
c abnormal movements givesphysicians additional clues to identify a speci
c aetiology,pathophysiologic mechanism, and speci
c treatment protocolsin certain subgroups of populations. The combination of morethan one type of hyperkinetic movements (eg, stereotypy anddystonia) strongly suggests the diagnosis of TD.
The most compelling evidence supporting the associationbetween neuroleptics and TD comes from epidemiologic studies.In general, TD is the most frequently observed disorder in TS.These studies have also determined risk factors, including age,duration of treatment, and gender. While the prevalence of TDvaries widely in the literature, re
ecting the heterogeneity of thegroups being observed as well as the various assessmentmethods used, an average prevalence among neuroleptic treatedpatients, corrected for the prevalence of spontaneous dyskinesia,is estimated to be between 20
In addition to TD, thereare few studies about prevalence of other movement disorders aspart of TS. Tardive dystonia has a prevalence of between 2
16%of neuroleptic treated patients.
10 11
The prevalence of tardiveakathisia, tics, myoclonus, and tremor have been reported as22%, 4%, 1%, and 30%, respectively.
 Ageing appears to be a critical risk factor for developing TD, asthe incidence increases from 5% in the younger age group(
40 years old) to 12% or higher in the older age group(
40 years old).
In general, at least 20% of patients treatedwith typical neuroleptics are affected with TD and approxi-mately 5% are expected to develop TD during each year of neuroleptic treatment. Female gender may be a risk factoralthough this is not supported by incidence studies. Patients withexisting movement disorders are at greater risk of developing TDwith continued use of antipsychotics. Total neuroleptic load, thedose and duration of use, is considered to be a risk factor.Neuroleptics, both typical and atypical agents, induce the upre-gulation of D
receptor binding, which is associated with thedevelopment ofTD. However,typical neuroleptics carry agreaterrisk than atypical agents.
Indeed, all atypical neurolepticshave a high serotonin-to-dopamine receptor blockade ratio in thebrain, and this high serotonergic blockade is thought to play a role in reducing acute extrapyramidal symptoms. Otherreported risk factors are race, a diagnosis of a mood disorder,cognitive impairment, the presence of negative symptoms,alcohol and substance abuse, the use of antiparkinsonian agentsand lithium, early extrapyramidal symptoms, illness awareness,diabetes, and lastly, HIV seropositive status
(box 3).
Classical TD
Classical TD comprises a phenomenologically distinct syndromeof TS, is the most common persistent adverse reaction toprolonged neuroleptic medication, and was the
rst to be iden-ti
ed. General characteristics are frequently observed to resemblenormal movement patterns, such as chewing (rumination),bridling (retraction of the corners of the mouth), grasping or
movements; however, patients perform thesemovements involuntarily. Orofacial movements especially may be temporarily suppressed by patients themselves or whenengaged in voluntary activities, such as talking or chewing.Interestingly, many patients with classical TD do not evennotice their involuntary movements unless their attention isdrawn to them by others.The facial muscles, particularly the perioral and oral muscles,are commonly affected in classical TD.
4 17
Dyskinesia of the
Box 1 Drugs that are commonly associated with tardivesyndromes
1. Phenothiazinesa. Chlorpromazineb. Triflupromazinec. Thioridazined. Mesoridazinee. Trifluoperazinef. Prochlorperazineg. Perphenazineh. Fluphenazinei. Perazine2. Thioxanthenesa. Chloprothixeneb. Thiothixene3. Butyrophenonesa. Haloperidolb. Droperidol4. Diphenylbutylpiperidinea. Pimozide5. Dibenzazepinea. Loxapine6. Dibenzodiazepinea. Clozapineb. Quetiapine7. Thienobenzodiazepinea. Olanzapine8. Substituted benzamidesa. Metoclopramideb. Tiapridec. Sulpirided. Clebopridee. Remoxipridef. Veralipride9. Indolonesa. Molindone10. Pyrimidinonea. Risperidone11. Tricyclic antidepressantsa. Amoxapine12. Calcium channel blockersa. Flunarizineb. Cinnarizine
Box 2 Classification of tardive syndromes
1. Tardive dyskinesia2. Tardive stereotypy3. Tardive dystonia4. Tardive akathisia5. Tardive tourettism6. Tardive myoclonus7. Tardive tremor8. Tardive parkinsonism
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tongue is characterised by a slow and repetitive retraction, ora sweeping tongue movement within the oral cavity, producinga bulge in the cheek, referred to as the
bonbon sign
 When thepatient is asked to extend the tongue, irregular, worm-likecontractions of the tongue muscles are frequently observed.Grimacing, with a lifting or arching of eyebrows or frowning,can also be a symptom of classical TD. Most patients exhibituncoordinated
exion/extension movements of individual
ngers, somewhat resembling guitar or piano playing move-ments. Dyskinesias of the legs
stamping movements
givethe impression of slowly walking in place or shifting bodweight from one foot to the other.
Dyskinesia of thediaphragm may lead to an irregular, uneven rhythm of speech oruncontrollable grunting and groaning. Other movements thathave been described in classical TD include hip-rocking move-ments, to-and-fro movements of the upper torso, head nodding,and
exion/extension movements of the toes, wrists, and ankles.
Tardive stereotypy 
Stereotypy, which is de
ned as a seemingly purposeful, coordi-nated but involuntary, repetitive, ritualistic gesture, mannerismor utterance, was reported by Stacy 
et al
19 20
and Miller
et al
tobe the most common form of TD. Some experts suggested thattardive stereotypy is probably a more appropriate term thanclassical TD to describe the repetitive, rather than random,movements. However, the stereotypic movements in classicalTD are very characteristic and similar in almost all patients withthis disorder, differentiating it from other types of stereotypiesseen in patients with autism and psychosis.
Tardive dystonia
Since the earliest reports of TD, a variety of involuntarmovements, in addition to the well known oro-buccal-lingualmasticatory movements, have been described, includingdystonia. The term
tardive dystonia
was de
ned by Burke
et al
to represent an involuntary movement predominated by dystonia and associated with the use of DRBAs.
For reasonsnot fully understood, young adults seem to be particularlsusceptible to this disorder.
 According to Burke
et al
, dystoniamust be present for more than a month and occur either duringongoing treatment with a DRBA or within 3 months of itsdiscontinuation.
 Although choreiform movements may occur,the principal movement must be dystonia. Dystonic movementsin tardive dystonia are strikingly different from the classical TD.Firstly, dystonic movements, de
ned as a syndrome of sustainedmuscle contractions frequently causing twisting and abnormalpostures, tend to be action speci
c. They occur consistentlwith certain actions and do not exhibit clear-cut periodicity asclassical TD. Secondly, many patients with dystonia note thattheir movements can be partially controlled by simple tactilemanoeuvres, termed sensory tricks or
geste antagoniste
, suchas touching the chin to alleviate torticollis.
Third, tardivedystonia occurs more often among men than women, the genderat greater risk for classic TD.
Finally, the shorter duration forneuroleptic exposure develops tardive dystonia and it tends tooccur in populations with a lower age of onset when comparedwith other TS.
10 26 
 Without a reliable history, tardive dystonia may be indistin-guishable from idiopathic torsion dystonia, including sensory tricks and distribution of dystonia. However, there are somedifferent features for identi
cation of these disorders (table 1).Tardive dystonia has a special predilection for cranial andcervical muscles. When it affects the neck, it usually results inretrocollis (
gure 1), in contrast to laterocollis or torticollis inidiopathic cervical dystonia. When involving the trunk, itusually produces severe scoliosis or opisthotonic posturing(
gure 2). When involving the upper limbs, internal rotation of the arms, extension of the elbows, and
exion of the wrists arecommon postures in tardive dystonia.
The legs are only infrequently involved. Tardive dystonia often occurs with otherTS, while idiopathic torsion dystonia rarely does.
Tardive akathisia
 Akathisia refers to a feeling of inner restlessness and jitterinessthat is often manifested by semi-purposeful movements.Subjectively, the most common complaint is the inability tokeep the legs still which are associated with vague inner tension,unease, or anxiety. Objectively, patients are seen rocking fromfoot to foot, walking in place, grunting, moaning, or trunkrocking. In addition to its common occurrence as an acuteadverse effect of neuroleptics, akathisia can become chronic(tardive akathisia).
Not surprisingly, tardive akathisia usually coexists with classic TD. The mean age of onset is 58 years, asthe age of onset of patients to whom neuroleptics are adminis-tered typically is younger than those taking other agents.
Box 3 Risk factors of tardive syndromes
1. Older age (young age in case of tardive dystonia)2. Female gender3. African American population4. Typical neuroleptics5. Higher dose and longer duration of neuroleptic use6. Pre-existing mood disorders7. Cognitive impairments8. Presence of negative symptoms9. Alcohol and substance abuse10. Use of antiparkinsonian agents and lithium11. Early extrapyramidal symptoms12. Diabetes13. HIV seropositive status
Table 1
A comparison of tardive dystonia and idiopathic torsion dystonia
Clinical features Tardive dystonia Idiopathic torsion dystonia
Cervical dystonic posture Retrocollis Torticollis, laterocollisAxial dystonic posture Opisthotonic posturing Lateral twisting of trunkUnique characteristics: internalrotation of the arms, extension of theelbows, and flexion of the wristsFrequent in young men NoneLeg involvement Less frequent Frequent in primary generalised dystoniaDystonia after voluntary action Reduced ExacerbatedCoexist with other tardive syndromes Frequent None
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