Journal of the Neurological Sciences 389 (2018) 35–42

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Journal of the Neurological Sciences

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Review Article

Tardive syndromes☆ T
⁎
Daniel Savitt, Joseph Jankovic
Parkinson's Disease and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, United States

A R T I C L E I N F O A B S T R A C T

Keywords: Tardive syndromes are a group of hyperkinetic and hypokinetic movement disorders that occur after some delay
Tardive syndromes following exposure to dopamine receptor blocking agents such as antipsychotic and anti-emetic drugs. The
Tardive dyskinesia severity of these disorders ranges from mild to disabling or even life-threatening. There is a wide range of
Dopamine receptor blocking agents recognized tardive phenomenologies that may occur in isolation or in combination with each other. These
Neuroleptics
phenomenologies include stereotypy, dystonia, chorea, akathisia, myoclonus, tremor, tics, gait disorders, par-
Stereotypy
kinsonism, ocular deviations, respiratory dyskinesia, and a variety of sensory symptoms. Recognition of the
Dystonia
various tardive phenomenologies may not only lead to early diagnosis but also to appropriate therapeutic in-
tervention. This review focuses on the diagnosis and clinical course of tardive syndromes and how to distinguish
between the various phenomenologies as well as how to differentiate them from other, similar but etiologically
different, movement disorders.

1. Introduction
The term “dyskinesia” refers to any abnormal involuntary move-
ment, but when it occurs after exposure to dopamine receptor blocking
agents (DRBAs), also referred to as “neuroleptics,” the diagnosis of
tardive dyskinesia (TD) should be considered. Tardive syndromes (TS)
represent a group of movement disorders that include stereotypy,
dystonia, chorea, akathisia, myoclonus, tremor, or tics, but may also
include other movement disorders, such as parkinsonism, gait dis-
orders, ocular deviations, respiratory dyskinesia, and a variety of sen-
sory symptoms [1]. There are other drug-induced movement disorders,
such as various tremors, myoclonus, akathisia, acute dystonic reaction,
drug-induced parkinsonism, and neuroleptic malignant syndrome
(NMS), that are not necessarily tardive as they occur during treatment
with the offending drug and typically resolve shortly after the drugs are
discontinued. Withdrawal emergent syndrome is a transient hyperki-
netic disorder that occurs after the DRBA is discontinued. The term
“extrapyramidal syndrome” or EPS, often used especially in the psy-
chiatric literature, should be abandoned as it lacks specificity and
wrongly implies involvement of system other than pyramidal [1]. In
this review we will focus on phenomenologies associated with TS
[Table 1].
Faurbye coined the term “tardive,” in 1964 to emphasize the delay
between treatment with a DRBA and the onset of abnormal movements
[2]. In his original report, 109 of 417 female hospitalized psychiatric
patients were found to have drug-induced dyskinesia [2]. Dyskinetic
movements were defined as, “coordinated, involuntary, stereotyped,
rhythmic movements”. Eight patients with a pronounced and consistent
“bucco-lingo-masticatory triad” were selected for detailed neurologic
examination. This neurologic examination showed that the dyskinetic
movements were strikingly stereotyped in the individual patient, the
pattern of dyskinesia was much the same in all the patients, and the
patients had not themselves noticed the dyskinetic movements. It is
important to note, however, that patients with psychosis, such as
schizophrenia and catatonia, had been described as manifesting ab-
normal involuntary movements, particularly stereotypies and perse-
verative behaviors, even before the advent of DRBAs [3–5].
The Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition (DSM-5) classifies TD as “involuntary movements (lasting at
least a few weeks) generally of the tongue, lower face and jaw, and
extremities (but sometimes involving the pharyngeal, diaphragmatic, or
trunk muscles), developing in association with the use of a neuroleptic
medication for at least a few months” [6]. According to DSM-5, in order
to make a diagnosis of TD the movement disorder must persist for at
least 1 month after the offending medication is discontinued [Table 2].
Although tardive movement disorders usually appear after months
or years of treatment with DRBAs, rarely they can occur even after a
brief exposure (e.g., several hours or days) and may be initially

☆
This manuscript is part of the Special Issue Tardive Syndromes and Their Management edited by Robert A. Hauser and Daniel D. Truong.
⁎
Corresponding author at: Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, 7200 Cambridge, Suite 9A, Houston, TX
77030-4202, United States.
E-mail address: josephj@bcm.edu (J. Jankovic).
URL: http://www.jankovic.org (J. Jankovic).

https://doi.org/10.1016/j.jns.2018.02.005
Received 6 January 2018; Accepted 2 February 2018
Available online 05 February 2018
0022-510X/ © 2018 Published by Elsevier B.V.

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D. Savitt, J. Jankovic Journal of the Neurological Sciences 389 (2018) 35–42

Table 1
Phenomenology of tardive syndromes.

Tardive syndrome Description

Classic tardive dyskinesia O-B-L stereotypy. Complex, repetitive, chewing movement, sometimes with lip smacking, pouting, opening and closing of the mouth, and
tongue protrusion. May interfere with speaking, chewing, and swallowing and may cause social embarrassment. May lead to tongue
hypertrophy (macroglossia). Trunk and limbs may be affected, usually in association with O-B-L stereotypy. Limb involvement is typically
distal with a repetitive, stereotypic pattern.
Tardive dystonia May occur as focal, segmental or generalized dystonia; more common in young men. Typically presents as blepharospasm, OMD, retrocollis,
trunk hyperextension (opisthotonus), and arm extension and pronation with wrist flexion.
Tardive akathisia An inner sense of restlessness with inability to be still. Body rocking movement, shifting weight from one foot to another, walking in place,
crossing/uncrossing the legs, or body rocking. May be associated with moaning or repetitive touching. Often disabling and difficult to treat.
Tardive myoclonus Prominent postural, spontaneous or stimulus-sensitive jerk-like movements, particularly in the upper extremities during sustained posture or
during voluntary movement (intention myoclonus).
Tardive tremor Postural and/or resting tremor, 3–5 Hz. Improves with dopamine depleters.
Tardive tics Motor or phonic tics with onset in adulthood. Can be identical to tics associated with Tourette syndrome.
Tardive chorea Random, jerk-like movements that flow from one body region to the next in an unpredictable, random, manner.
Tardive gait Gait changes may be “dance-like,” taking short steps on toes followed by longer strides, or “duck-like” with wide-based, unsteady gait with
short stride length and steppage pattern.
Tardive parkinsonism Rest tremor, bradykinesia, rigidity persisting for months/years after discontinuation of DRBAs. DaTscan is typically normal.
Withdrawal emergent syndrome Generalized choreiform movements mainly of the neck, trunk, and limbs in children after sudden cessation of DRBAs. A self-limited condition.
Tardive ocular deviation Conjugate eye deviations characterized by a fixed stare followed by conjugate spasmodic movements of the eyes, generally in an upward
direction. Not typically painful, in contrast to oculogyric crises in acute dystonic reaction.
Tardive pain Chronic, often burning, pain or unpleasant sensation in the oral or genital regions.

O-B-L = oral-buccal-lingual, DaTscan = dopamine transporter scan, DRBA = dopamine receptor blocking agent.

Table 2 declining, most likely due to early recognition, clinicians must be vig-
Tardive dyskinesia: DSM-5 and ICD-10 CM codes [6]. ilant about the early features of the syndrome in order to institute

• Tardive
dyskinesia: G24.01
• Involuntary movements (lasting at least a few weeks) generally of the tongue,
lower face and jaw, and extremities (but sometimes involving the pharyngeal,
diaphragmatic, or trunk muscles), developing in association with the use of a
neuroleptic medication for at least a few months. Tardive syndrome involves
movement problems which are distinguished by their late emergence in the
course of treatment and their potential persistence for months to years, even in
the face of neuroleptic discontinuation or dosage reduction.
• Tardive dystonia: G24.09
• Tardive akathisia: G25.71
• Medication-induced acute dystonia: G24.02
• Medication-induced acute akathisia: G25.71
• Medication-induced postural tremor: G25.1
• Other medication-induced movement disorder: G25.79
manifested by acute, transient, abnormal movements. To be considered
TS, these abnormal movements must persist for at least 1 month after
discontinuation of the DRBA. In contrast, the acute, DRBA-induced
syndromes resolve within one month of discontinuation. These acute
syndromes include acute dystonic reaction, acute akathisia, drug-in-
duced parkinsonism, and NMS [7]. Acute dystonic reaction is generally
the earliest abnormal involuntary movement to appear after initiating a
DRBA. In about half of cases, the acute dystonic reaction occurs within
48 hours and in 90% within 5 days of treatment [7]. All agents that
block dopamine D2 receptors can induce acute dystonic reactions, ty-
pically manifested by painful ocular deviations (oculogyric crises), or-
omandibular dystonia, particularly manifested by dystonic jaw
opening, and cervical dystonia such as retrocollis and torticollis [8,9].
Akathisia refers to a subjective sense of unease or restlessness and a
feeling or the need to move without ability to sit, stand or lie still [10].
It may be accompanied by anxiety and agitation and manifested by
stereotypic movements such as touching the face or scalp and tramping
movements of the legs and feet. Akathisia can occur as an acute side
effect of DRBA therapy (acute akathisia) or as a tardive phenomenon
(tardive akathisia), depending on how long the akathisia persists after
discontinuation of the DRBA, as discussed below. Akathisia is one of the
most disabling and difficult-to-treat forms of TD, but propranolol, an-
ticholinergics, clonazepam and mirtazapine may be helpful [11–13].
NMS is potentially a life-threatening disorder, manifested by acute
changes in mental status, muscle rigidity, hyperthermia, and autonomic
dysfunction [14]. Although the NMS-related mortality rates have been
emergency intervention [15].
Individuals who experience DRBA-triggered acute movement dis-
orders have a greater risk of developing TS [16]. By definition, TS are
iatrogenic disorders and, therefore, the diagnosis cannot be made in the
absence of exposure to DRBAs. When suspicion is high, based on typical
phenomenology, careful examination of medical and pharmacy records
should be performed to exclude prior exposure.
2. Drugs known to cause tardive syndromes
TS are caused by a variety of drugs used in the treatment of psy-
chiatric, gastrointestinal, and other disorders, all of which are DRBAs.
The original antipsychotic drugs, also named “typical” or first-genera-
tion agents (FGAs), include medications such as chlorpromazine, ha-
loperidol, fluphenazine, thioridizine, and pimozide. They act primarily
as dopamine D2 receptor antagonists and their clinical potency is often
highly correlated with their affinity for the dopamine D2 receptor [17].
Second-generation agents (SGAs), also termed, the “atypical” anti-
psychotics, block dopamine D2 receptors but they dissociate from the
receptors more rapidly and also act on serotonin 5-HT2A and other re-
ceptors. Examples of drugs in this class include clozapine, quetiapine,
olanzapine, and risperidone, but the classification of the latter as an
SGA has been challenged as this drug acts more like an FGA. Third-
generation antipsychotic agents (TGAs) work via partial agonism of
presynaptic D2 autoreceptors [17]. These autoreceptors are now known
to contain high densities of D2 and low densities of D3 receptors. When
activated, the autoreceptors decrease the synthesis and release of do-
pamine as well as reduce the firing of dopaminergic neurons. A partial
D2 agonist is thought to activate the presynaptic receptors. Aripiprzole
is the prototypical third- generation antipsychotic and the recently
approved brexipiprazole and cariprazine also share the mechanism of
partial D2 agonism [18].
The term “atypical” was introduced to describe agents with a
minimal risk of causing TS. Of the available SGAs, clozapine and que-
tiapine showed the lowest propensity to cause movement disorders
[19]. Both clozapine and quetiapine have poor affinity for the dopa-
mine D2 receptor, which probably accounts for their lower risk for
parkinsonism and TS compared to other “atypical” antipsychotics.
DRBAs other than antipsychotics that are known to cause TS include,
but are not limited to, anti-emetics (metoclopramide and

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D. Savitt, J. Jankovic
promethazine), certain tetracyclic antidepressants (amoxapine), and
select calcium channel blockers (flunarizine and cinnarizine) [12].
Metoclopramide is the non-antipsychotic medication most commonly
responsible for TS, possibly due to non-selective blockade of D2 re-
ceptors in the striatum [20–22]. The frequency of metoclopramide-in-
duced TS has been gradually declining after 2009 when the US Food
and Drug Administration issued “black box warning” increased
awareness about this condition among gastroenterologists and other
physicians who used to prescribe the drug for a variety of gastro-
intestinal problems [22].
TS has not been shown to be caused by dopamine depleters, such as
the vesicular monoamine transporter 2 (VMAT2) inhibitors, of which
tetrabenazine has been used in the treatment of a variety of hyperki-
netic disorders for many decades [23]. Indeed, VMAT2 inhibitors
deutetrabenazine and valbenazine were approved in 2017 by the US
Food and Drug Administration (FDA) for the treatment of TD.
3. Epidemiology of tardive syndromes
The incidence of TS is estimated to increase linearly by 5% annually
during the first 5 years of treatment, after which time it tends to pla-
teau; 49% after 10 years, and 68% after 25 years [24–26]. In one study,
TS occurred in 32.4% of patients treated with FGAs and in 13.1% with
SGAs [27]. In another review, the global mean prevalence of TS was
25.3% across all 41 studies involving 11,493 subjects (mean
age = 42.8 years, male = 66.4%), 77.1% of whom had schizophrenia-
spectrum disorders [28]. Prevalence rates were lower with exposure to
SGAs (20.7%) versus FGAs (30.0%) (p = 0.002). Furthermore, longer
duration of illness and the presence of parkinsonism were associated
with higher prevalence of TS. Although the SGAs and TGAs have been
marketed as having low risk of TS, all of them have been associated
with TS, with the possible exception of clozapine. For example, ar-
ipiprazole, considered a TGA because it also acts as a partial dopamine
receptor agonist [24], can cause TS [29]. In a series of patients followed
at the Movement Disorders Clinic at Baylor College of Medicine be-
tween January 2002 and January 2010, aripiprazole was associated
with TS in 8 of 236 (3.4%) patients [29]. Because of its expanding on-
label as well as off-label use, aripiprazole is becoming increasingly re-
cognized as a cause of TS [30–32].
4. Clinical course and prognosis
The symptoms of TS typically emerge after 1–2 years of continuous
exposure to a DRBA and almost never before 3 months [33]. The se-
verity of TS is quite variable, ranging from mild and unnoticed by the
patient to disabling and even life threatening (e.g. esophageal dyski-
nesia, respiratory dyskinesia). Symptoms typically begin with an in-
sidious onset, evolving to a full syndrome over days to weeks following
onset. This is followed by a stabilization of symptoms in a chronic, but
sometimes waxing and waning course [11].
TS can persist for years after discontinuation of the offending agent,
although some patients can experience partial or complete remission of
symptoms a few years after discontinuation of the causative agent.
Reported remission rates have varied across studies depending on the
definition of remission and duration of follow-up, ranging from 0 to
73%, but most studies report remission rates to be lower than 25% [34].
The natural history of TS, however, has not been well studied because
patients often continue their therapy with DRBAs chronically for
symptomatic treatment of their underlying psychiatric illness or even to
treat their TS. Furthermore, prospective longitudinal follow up over
years or decades is usually lacking. A retrospective study published in
2014 involving 106 patients with TS in whom DRBAs were completely
withdrawn found a spontaneous remission rate of only 2% [35]. The
average follow-up time was 3.1 ± 3.4 years (range 0–13.52 years).
Limitations of the study, acknowledged by the authors, included the
retrospective nature, the selection bias of a Movement Disorders Center
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Journal of the Neurological Sciences 389 (2018) 35–42
that has a tendency to see mostly refractory cases, and the presence of a
large proportion of patients lost to follow up. These limitations may
have led to an underestimation of TS remission rates. Several studies
have found that the chances of remission decrease with longer duration
of exposure to DRBAs prior to discontinuation [36]. In a prospective
study of 49 patients who discontinued the offending agent, 20% had
symptomatic improvement and 2% had complete remission of tardive
symptoms during a mean of 40 weeks of follow up (range 1–59 months)
[37].
Withdrawal of the offending agent, particularly when abrupt, can
exacerbate the movements, presumably because of removal of dopa-
mine receptor blockade [38]. Conversely, increasing the dose can help
ameliorate the symptoms by increasing the blockade. These observa-
tions support the prevailing theory for the pathophysiology of TD, that
chronic use of DRBAs results in gradual hypersensitization of dopamine
receptors. Movements that disappear with resumption of DRBAs (or
with an increase in dose) have been termed “masked tardive dyski-
nesia” [39]. “Covert dyskinesia” refers to a masked form of TD that is
observed only after antipsychotic drugs are withdrawn or their dosage
is reduced. Withdrawal dyskinesia appears under similar circumstances,
but remits spontaneously in 6 to 12 weeks [40]. This should be differ-
entiated from withdrawal emergent syndrome (see below).
The diagnosis of various forms of TS is based on history of DRBA
exposure and on clinical observation of phenomenology. There is no
diagnostic or progression biomarker for TS. It is considered prudent
practice to document the patient's neurological examination before
initiation of DRBA therapy and obtain informed consent. The American
Psychiatric Association issued guidelines for management of schizo-
phrenia and recommended that patients should be clinically assessed
for abnormal involuntary movements every 6 months if taking an FGA
and every 12 months if taking an SGA or more frequently if there are
factors known to increase the risk of TD, such as advanced age in
women, bipolar disorder, history of diabetes mellitus, brain trauma,
and alcohol or drug abuse, and prior adverse reaction to DRBA [41]. In
addition, periodic evaluation using the Abnormal Involuntary Move-
ment Scale (AIMS) is advisable [41–43]. Although the scale has many
limitations it is useful in recording signs associated with TS and it has
been used as the primary outcome measure in various clinical trials in
TS.
5. Tardive stereotypy
Tardive stereotypy is the term applied to describe seemingly pur-
poseful, repetitive, and coordinated movements that sometimes give
the appearance of ritualistic gestures or mannerisms. Oral-buccal-lin-
gual (O-B-L) stereotypy is the most typical manifestation of “classic TD”
or tardive stereotypy [44–45] (Video 1). This movement disorder must
be differentiated from other orofacial stereotypies such as edentulous
dyskinesia [46], and other movement disorders such as oromandibular
dystonia (OMD), Huntington disease (HD), and neuroacanthocytosis
[47]. The limbs and trunk may also be affected, but usually in asso-
ciation with the O-B-L dyskinesias. The involuntary mouth movements
of O-B-L stereotypy are typically manifested by a repetitive, complex
chewing motion, sometimes with lip smacking, opening of the mouth,
and tongue protrusion [48]. These movements are predictable and
patterned. When asked to do so, patients can suppress the mouth
movements but when patients are distracted, such as when asked to
perform repetitive movements with their hands or feet, the O-B-L dys-
kinesia often increases. The movements may also cease when the pa-
tient is talking, putting food in the mouth, or when a finger is placed on
the lips. However, when a patient is asked to keep the tongue still inside
the mouth, it tends to assume continuous athetoid, coiling movements.
Occasionally, the tongue rapidly and repetitively protrudes from the
mouth, leading to the “fly-catcher's tongue”. Macroglossia caused by
tongue muscle hypertrophy can result from the continuous involuntary
movements. In contrast to HD, the forehead and eyebrows are rarely
D. Savitt, J. Jankovic
involved in patients with TD [49]. The upper facial chorea of HD is
characterized by brief, irregular widening of palpebral fissures and in-
termittent, irregular blinking. Furthermore, the choreic movements in
HD are random and not as predictable or patterned as those in classic
TD. Additionally, patients with classic TD are able to maintain tongue
protrusion for a much longer time than patients with HD, who typically
have motor impersistence. TD may have dental complications, as it can
cause attrition of natural teeth, and when associated with OMD it can
cause bruxism-related dental damage and secondary tempor-
omandibular joint syndrome [50]. It may also worsen the stability of
dentures and increase the risk of prostheses breaks.
When the limbs are involved in TD, it is typically the distal parts
that are affected. These movements also display a repetitive, stereotypic
pattern, for example the so-called “piano playing fingers” [7]. A rare
presentation of limb involvement in classic TD is stereotyped hand
clasping, as reported in an 83-year-old woman after 18 months of ex-
posure to neuroleptics [51]. Stereotypic, thrusting movements of the
trunk and pelvis may present as “copulatory dyskinesia”. Respiratory
pattern also can be affected in classic TD. In one survey of 351 hospi-
talized adult psychiatric patients, respiratory TD was present in eight
subjects (2.3%). All these subjects also had O-B-L dyskinesias. In one of
these patients, the respiratory irregularities led to recurrent episodes of
aspiration pneumonia [52]. This respiratory pattern is characterized by
irregular tidal breathing, causing hyperventilation at times and hypo-
ventilation at other times, producing greater variability in the tidal
volume as well as the time length of the total respiratory cycle. In
general, classic TD patients with respiratory dysrhythmias have rapid,
shallow breathing, often wrongly attributed to anxiety, sometimes as-
sociated with shortness of breath and compromised exercise perfor-
mance [53]. In one report, two patients were noted to have esophageal
dyskinesias confirmed by esophageal contrast radiography and eso-
phageal manometry [54]. One of these patients died due to asphyxia-
tion of food. Thus, this is a potentially life-threatening side effect of
antipsychotic therapy.
Rabbit syndrome, another form of TS, is important to recognize as it
may be confused with classic TD or facial tremor. Rabbit syndrome
consists of fine rhythmic movements at rest involving only the vertical
axis of the oral, perinasal and masticatory muscles at a frequency of
approximately 5 Hz, mimicking the chewing actions of a rabbit. There
may be an associated popping or smacking sound produced by the re-
petitive lip movements [55]. Although generally considered to be a rare
type of drug-induced parkinsonism, there have been reports of rabbit
syndrome as a tardive phenomenon [56]. The tongue is usually spared
in rabbit syndrome, a key differentiating characteristic from classic TD
[57].
6. Tardive dystonia
Dystonia was noted to be a complication of DRBA therapy as early as
1962 [58]. Initially described as an acute phenomenon, dystonia was not
recognized as a form of TS until 20 years later [59]. Tardive dystonia is
important to recognize because it has a different pharmacologic response
from that of classic TD. For example, anticholinergic medications, such as
trihexyphenidyl, can have an ameliorating effect on tardive dystonia but
these drugs may trigger or exacerbate classical TD [7].
Table 3
Tardive versus primary dystonia.
Tardive dystonia
Typically affecting young males, mean age 40 years
Retrocollis, truncal dystonia with opisthotonic posturing, arm extension with
pronation
Often associated with stereotypies, akathisia and other hyperkinetic disorders
Alleviating maneuvers are not common
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Journal of the Neurological Sciences 389 (2018) 35–42
Tardive dystonia can occur at all ages, but is more common in po-
pulations younger than that affected by TD. The mean age at onset is
40 years old, compared to idiopathic dystonia, which shows a bimodal
age distribution with an early peak in childhood and a later peak in
adulthood [7]. Unlike classic TD, which tends to occur in older females,
tardive dystonia tends to occur in young males [20]. The risk of de-
veloping tardive dystonia starts at the initiation of therapy without any
safe minimum period of exposure [60]. There are varying reports re-
garding remission rates. In a review of 32 patients with tardive dys-
tonia, none of the patients achieved complete remission during a mean
follow-up period of 4.9 years (range 1–10 years) [61]. Van Harten and
colleagues reported a remission rate of 80% in mild cases of tardive
dystonia; however, the patients remained on antipsychotic medications,
thus the tardive dystonia may have been masked and, therefore, the
underlying symptoms may have reappeared with withdrawal of the
offending agents [62].
The distribution of tardive dystonia appears to be dependent on age
at onset (childhood versus adult-onset). Kang et al. found a correlation
showing that the site of onset ascended from the lower extremities to
the face as age at onset increased [36]. Even in young children, how-
ever, tardive dystonia rarely affects the lower extremities alone. This is
in contrast to primary dystonia, in which patients with a younger age of
onset are more likely to develop generalized dystonia, whereas adult
onset patients are more likely to have cranio-cervical dystonia or seg-
mental dystonia [60].
Regardless of the age at onset, tardive dystonia typically progresses
from a focal onset to more widespread distribution over a period of
months to years. In one series, only 17% of cases of tardive dystonia
remained focal at the time of maximum severity [36]. The onset of
tardive dystonia after exposure to a DRBA is widely variable, ranging
from a few days to 23 years [36]. Men tend to develop tardive dystonia
after a shorter exposure as well as at a younger age than women [36].
The phenomenology of tardive dystonia is so characteristic that the
diagnosis should be considered even in the absence of a history of ex-
posure to DRBAs. The typical phenomenology of tardive dystonia
consists of retrocollis, opisthotonic posturing, and extension of arms at
the elbow, internal rotation at the shoulders, and flexion of the wrists
[60] (Video 2). In one case the retrocollis was severe enough to cause a
fracture of the odontoid process [63]. Table 3 compares and contrasts
features of tardive dystonia versus primary dystonia.
Both primary oromandibular (OMD) and tardive OMD occur more
commonly in women, with the most common manifestation being jaw-
closing dystonia with or without associated bruxism [64]. In primary
OMD, the patient is more likely to have coexisting cervical dystonia.
The combination of limb stereotypies, akathisia, and respiratory dys-
kinesia is only seen in tardive OMD and not in primary OMD. Both
primary and tardive OMD respond well to botulinum toxin injections.
Tardive dystonia can sometimes be severe enough to cause life-
threatening dysphagia. This was described in one case due to metoclo-
pramide [65] and in another two cases due to other neuroleptics [66].
Many patients with tardive dystonia develop tardive O-B-L stereo-
typy at some point in their course [60,67]. It is not clear why some
individuals develop tardive dystonia versus classic TD versus both, al-
though it has been noted that the dystonia tends to be more severe
when both are present [60,68].
Primary dystonia
Bimodal age distribution with peaks in childhood and adulthood
Generalized dystonia in children and cranial-cervical dystonia in adults
Occurs in isolation, without other movement or neurologic disorders
Alleviating maneuvers (sensory tricks, geste antagoniste) typically relieve the abnormal
posture
D. Savitt, J. Jankovic
7. Tardive akathisia
Akathisia is defined as a feeling of inner restlessness and jitteriness
resulting in an inability to sit or stand still. Manifestations of tardive
akathisia include marching in place, leg crossing/uncrossing, truncal
rocking, respiratory grunting and moaning, and complex hand move-
ments, such as face or scalp rubbing or scratching [69]. “Pseudoa-
kathisia” refers to the appearance of extreme restlessness in the absence
of a clear subjective feeling of restlessness. Although originally thought
of as an acute or subacute side effect of DBRAs, it became apparent in
the early 1980s that akathisia can also occur as a late side effect of
antipsychotic therapy and could persist despite its discontinuation,
hence the term “tardive akathisia” [70–72]. Tardive akathisia can be
accompanied by classic TD [73–75].
The mean age at onset for tardive akathisia is 58 years old, ranging
from 21 to 82 years, similar to classic TD [74]. The mean duration of
DRBA exposure before onset was 4.5 years, with a range from 2 weeks
to 22 years. Over half of patients had onset within 2 years of exposure.
In the original series of patients with tardive akathisia, all patients had
either TD (93%) or tardive dystonia (33%) or both (27%). However,
isolated tardive akathisia can be a presenting manifestation.
Tardive akathisia can be focal or generalized. Focal akathisia con-
sists of discomfort in one local area, often associated with an urge to
move that body part. Generalized akathisia is typically manifested by
an uncomfortable body sensation that the patient alleviates with a
semipurposeful, unvoluntary (the desire to perform the action builds
until it is no longer suppressible), stereotypic movement, such as re-
petitive touching. Patients often exhibit rocking or swaying movements,
walking in place, and crossing/uncrossing of the legs [76]. The clinical
phenomenology is thought to be the same as acute akathisia, although
moaning and focal pain tend to be more common in tardive akathisia
[74]. Tardive akathisia must be differentiated from other stereotypies,
including the leg stereotypy syndrome, manifested by often life-long
repetitive, rhythmical, stereotypic leg movement, especially when sit-
ting or by swaying of body when standing [77,78]. Although it has an
appearance of restlessness, in contrast to tardive akathisia, leg stereo-
typy syndrome is not related to the use of DRBAs, may start in child-
hood, is often familial, and is not associated with an urge to move.
Tardive akathisia frequently persists for years and is often resistant
to therapy. In contrast to acute akathisia, which can improve with an-
ticholinergics, propranolol, clonazepam, and opioids, tardive akathisia
is generally resistant to pharmacologic therapy but may respond to
VMAT2 inhibitors [48]. It should be noted, however, that of the dif-
ferent subtypes of TS, tardive akathisia is often the most troublesome
and most difficult to treat.
8. Tardive myoclonus
Myoclonus is a brief, involuntary muscle contraction causing a jerk-
like movement. The first documented case of tardive myoclonus was in
a 46-year-old woman who developed a rhythmic, 1–2 Hz, jerk-like ex-
tension of the neck after a prolonged course of antipsychotic therapy
[79]. Tardive myoclonus usually presents as a prominent postural,
spontaneous or stimulus-sensitive, jerk-like movement in the upper
extremities [11,80]. Myoclonus usually occurs in the arms and
shoulders, most prominently when patients hold their hands up and
forward with the elbow joints flexed at approximately 90° or during
voluntary movement.
In one series, 23 of 60 patients with schizophrenia, who had been
taking neuroleptics for at least 3 months, were observed to have pos-
tural myoclonus [81]. Very few of these patients were even aware of the
movements. These patients were on significantly higher doses of neu-
roleptics than those without myoclonus. There was no significant cor-
relation between the occurrence of myoclonus and either parkinsonism
and other tardive phenomenologies. However, the myoclonus was fre-
quently associated with abnormal finger movements. These finger
39
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Journal of the Neurological Sciences 389 (2018) 35–42
movements were asynchronous, arrhythmic, repetitive, shock-like, and
small in amplitude. They also increased in amplitude when the hands
remained extended at the wrists.
9. Tardive tremor
Tardive tremor is quite rare and has been described in a few case
reports [48,82]. Tardive tremor typically appears after prolonged use of
DRBAs and persists long after their discontinuation. Similar to other
tardive syndromes, tardive tremor worsens after discontinuation of the
DRBA and is suppressed when treated with a DRBA or dopamine de-
pleting medication, distinguishing it from parkinsonian tremor [83].
The tremor described in patients exposed to neuroleptics and without
signs of parkinsonism includes a high amplitude, moderate frequency,
postural and resting tremor [82]. The frequency typically ranges from 3
to 5 Hz and is usually high in amplitude. In the absence of parkinsonian
features, it is often responsive to dopamine-depleting medications such
as tetrabenazine and other VMAT2 inhibitors. Tardive tremor has also
been reported with chronic use of metoclopramide [83]. In one case
report of metoclopramide-induced tardive tremor, the patient could
ameliorate the tremor by applying pressure with his own hand to the
back of his neck or by wearing a cervical collar [84]. The presence of an
alleviating maneuver in this case suggests that this limb tremor was
perhaps a form of dystonic limb tremor [85]. Tardive tremor does not
respond to parkinsonian or essential tremor therapies, but does respond
to antidopaminergic therapies, which further supports the existence of
this variant of tardive syndrome [48].
10. Tardive tics
Tics are defined as sudden, brief, intermittent, involuntary or semi-
voluntary movements (motor tics) or sounds (phonic tics). There are
usually premonitory sensations preceding motor or vocal tics. The most
common cause of tics is Tourette syndrome, chronic motor tic disorder,
and chronic phonic tic disorder; however, many other disorders are
known to cause tics including pervasive developmental disorders,
Down's syndrome, neuroacanthocytosis, and HD. Drugs, including CNS
stimulants, cocaine, and neuroleptics can be associated with tics as
adverse effects.
In a systematic review of tardive tic cases, 41 patients without a
previous tic disorder developed tics after exposure to antipsychotics,
anticonvulsants, antidepressants, stimulants, or other medications [69].
In 23 of the 41 (56%) cases, the occurrence of tics was attributed to
therapy with neuroleptics. The presence of concomitant TD was re-
ported in 10 of these 23 cases. There was a wide range of time to tic
appearance after exposure to these drugs, ranging from 2 months to
24 years. The tics improved or resolved after discontinuation of these
drugs. One report of a 59-year-old woman with longstanding schizo-
phrenia treated with a combination of oral chlorpromazine and depot
fluphenazine described development of tardive tics after 30 years of
exposure to this combination of medications [86]. This patient had no
history of tic disorder and her new tics included both phonic and motor
tics. Her motor tics and coprolalia completely resolved with dis-
continuation of the offending agents and institution of risperidone and
clonazepam to her medication regimen.
The term tardive tics or tardive tourettism is preferred over tardive
Tourette syndrome because not all of these cases meet criteria for
Tourette syndrome and the latter is an idiopathic disorder with a
marked familial component [87]. Other than older age at onset and
neuroleptic exposure, tardive tics are clinically indistinguishable from
the tics of Tourette syndrome.
11. Tardive chorea
Chorea is defined as involuntary, continual, abrupt, rapid, brief,
unsustained, irregular movements that flow from one body part to
D. Savitt, J. Jankovic
another. Patients can temporarily and partially suppress the movements
and commonly mask some of the movements by incorporating them
into semi-purposeful activity, known as parakinesia. Motor im-
persistence, the inability to maintain voluntary contraction such as with
manual grip and tongue protrusion, is characteristic of chorea.
Although previously referred to as “rhythmic chorea,” careful ex-
amination showed that most of these patients had stereotypy and that
tardive chorea as the only manifestation of TD is quite rare [45]. When
present, tardive chorea is usually accompanied by O-B-L stereotypy.
Because chorea is defined as a random jerk-like movement, the term,
“rhythmic chorea” is not appropriate as many TD patients actually have
stereotypy, rather than chorea [11]. Diagnostically, tardive chorea can
be challenging when patients with dementia and behavioral problems
are treated with neuroleptics and the diagnosis of HD or HD-like dis-
orders is often entertained. Clues pointing toward tardive chorea as the
diagnosis include the history of onset of chorea following the use of
DRBAs, lack of neuroimaging findings of HD, and negative genetic
testing for HD [88]. Phantom dyskinesia was reported as a tardive
phenomenon in a 58-year-old woman who had persistent post-ampu-
tation stump chorea and the perception of involuntary movements in
the phantom left arm [89]. Chorea can be seen in children with sudden
withdrawal from a DRBA as part of withdrawal emergent syndrome (see
below).
12. Tardive gait
Disorders of gait disorders have been recognized in patients with TD
for long time. Indeed, Faurbye used the term “tusikinesia” to describe
the incessant tripping and shuffling movements of the feet with in-
ability to stand still in patients with TD [2]. This characterization,
however, suggests akathisia in patients with TD while they stand, rather
than tardive gait. In a study of 42 patients with moderate to severe TD,
43% were found to have a peculiar gait and 21% had frankly abnormal
gaits [90]. Yassa described 6 of 22 (27%) TD patients during inpatient
consultations who had pelvic gyrations, severe pseudoakathisia of the
legs, and difficulty standing and moving from one place to the other
[91]. Lauterbach et al. described 59% of 31 hospitalized patients with
TD who had abnormal arm swinging, abnormal lower extremity gait,
peculiar truncal movements, and manneristic gaits [92]. Kuo and Jan-
kovic described 2 patients with a “duck-like gait” and one patient with a
dancing gait. The dancing gait was characterized by seemingly pat-
terned movements in the legs that could not be completely attributed to
tardive stereotypy in the legs alone. It involved taking short steps on the
toes that were followed by longer strides. The duck-like gait manifested
as a wide-based, unsteady gait with short stride length and steppage
pattern, and shifting weights when walking. Dystonia alone could not
explain these gait abnormalities because there were no signs of in-
creased muscle tone, involuntary muscle contraction of a specific
muscle group, and there were no alleviating maneuvers that could
improve the gait abnormalities [93]. Tardive gait is a relatively rare
phenomenon but awareness of this entity is important, as gait impair-
ment can be the main concern in these patients.
13. Tardive parkinsonism
Tardive parkinsonism is a controversial entity referring to parkin-
sonism that persists several months, years, or even indefinitely after
cessation of DRBA medications. The signs include those seen in idio-
pathic Parkinson disease, including asymmetric rest tremor, rigidity,
and bradykinesia. Some patients may have underlying Parkinson dis-
ease that becomes unmasked after DRBA exposure, supported by de-
creased dopamine transporter (DAT) density on 123I-ioflupane single-
photon emission computerized tomography (SPECT) or DaTscan
[94,95]. In contrast, true tardive parkinsonism can be diagnosed when
the parkinsonism persists for at least several months after dis-
continuation of DRBAs in the setting of a normal DAT SPECT. However,
40
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Journal of the Neurological Sciences 389 (2018) 35–42
while studies have shown that long-term use of antipsychotics had no
major effect on the density of dopamine terminals in patients without
TD, there was a reduction in patients who did have TD [96]. Ad-
ditionally, the normal loss of dopamine in healthy individuals was ap-
proximately 5% per decade, whereas the rate of cell loss was about 15%
per decade in schizophrenia patients with long-standing exposure to
antipsychotics.
Other than the history of DRBA exposure and co-occurrence of other
tardive phenomenologies, there are no other phenomenological fea-
tures that reliably differentiate tardive parkinsonism from other causes
of parkinsonism. The entity of tardive parkinsonism has not been well
defined and its existence is based on several case reports. In one such
case report, a 74-year-old woman with bipolar disorder was noted to
have tardive dyskinesia and parkinsonian symptoms, including rest
tremor, rigidity, bradykinesia, and gait disorder that persisted several
months after discontinuation of neuroleptics [97]. Post-mortem eva-
luation of her brain revealed no evidence of degeneration in the sub-
stantia nigra or other brainstem centers, no nigral or cortical Lewy
bodies, absence of glial cytoplasmic inclusions (characteristic of mul-
tiple system atrophy), and absence of globose neurofibrillary tangles
(seen in progressive supranuclear palsy). This case lends support to the
notion of tardive parkinsonism as a distinct, albeit very rare, entity,
given the absence of pathological findings supporting the diagnosis of
Parkinson disease as the underlying etiology. [98,99] Patients with
tardive parkinsonism, without underlying Parkinson disease, would be
expected to gradually improve after withdrawal of the offending DRBA.
This recovery could be accelerated by temporary treatment with do-
paminergic drugs or amantadine, but long-term data in this rare group
of TS is lacking.
14. Withdrawal emergent syndrome
Withdrawal emergent syndrome was first described in 1973 when it
was noticed that children abruptly withdrawn from chronic treatment
with antipsychotic medication developed choreiform movements re-
sembling Sydenham chorea [100]. Unlike classic tardive dyskinesia, the
movements involve mainly the neck, trunk, and limbs but in contrast to
classic TD, oral-buccal-lingual muscles are only rarely involved.
The condition, although often alarming, is self-limited and typically
remits with discontinuation of the offending agent, usually within a few
days [48]. If it persists beyond 4 weeks, it would be classified as TS. The
majority of children affected by withdrawal emergent syndrome do not
require treatment because of excellent prognosis for spontaneous re-
mission [101]. Slow tapering of DRBAs reduces the risk of withdrawal
emergent syndrome.
Abrupt withdrawal from chronic treatment with DRBAs in adults
may lead to withdrawal dyskinesia or transient TD. The dyskinetic
movements spontaneously remit after several weeks of discontinuation
of the offending agent. Treatment involves DRBA re-initiation with
gradual down-titration to prevent the recurrence of the withdrawal
emergent syndrome [102].
15. Tardive ocular deviations
Oculogyric crises are commonly seen as a manifestation of acute
dystonic reactions occurring immediately or shortly after exposure to a
DRBA. They typically consist of a painful deviation of the eyes in an
obliquely upward direction that may last several minutes or even hours.
This phenomenon has been also described in postencephalitic parkin-
sonism, Tourette syndrome, and other disorders, including those that
are associated with enzymatic defects in the dopamine-synthesizing
pathway [103,104]. Although we prefer the term tardive ocular de-
viations, the traditional term “oculogyric crises,” is often used to de-
scribe this condition even though the eye movements are not truly gyric
(rotary) nor do they typically manifest as a crisis. Tardive ocular de-
viations were first reported in 1981 in four cases of TD that persisted
D. Savitt, J. Jankovic
after prolonged exposure to phenothiazines [105] (Video 3). The ocular
movements typically consist of conjugate spasmodic movements of the
eyes with deviation in an upward direction that may be sustained for
several seconds or minutes.
16. Tardive sensory syndrome
In addition to movement disorders, patients with tardive syndrome
may develop various sensory symptoms, including an urge to move,
paresthesias, and pain [106]. Tardive pain was reported in 11 patients,
described by Ford et al. in 1994 as a chronic oral and genital sensation
in patients exposed to DRBAs who had tardive syndrome [107]. The
pain syndromes occurred in association with inner restlessness and
involuntary movements characteristic of tardive syndrome. In these
patients, the pain syndromes predominated over other neurologic
symptoms. The pain or discomfort, often localized to the mouth or
genitalia, is typically described as a burning, lancinating or blistering
sensation. In each case, a detailed evaluation failed to reveal an organic
etiology to explain the pain. Many of the patients had unsuccessfully
tried a variety of analgesics, including nonsteroidal anti-inflammatory
agents, acetaminophen, codeine, lidocaine injections, steroids, gaba-
pentin, carbamazepine, trihexyphenidyl, and tricyclic antidepressants.
Seven of these patients either had dramatic improvement or resolution
of symptoms with tetrabenazine or other VMAT2 inhibitors.
17. Conclusion
The primary aim of this review is to provide a comprehensive re-
view of TS, emphasizing the need for recognition of the broad range of
phenomenology of TD and other movement disorders related to ex-
posure to DRBAs. These phenomenologies include stereotypy, dystonia,
chorea, akathisia, myoclonus, tremor, tics, gait disorders, parkinsonism,
ocular deviations, respiratory dyskinesia, and a variety of sensory
symptoms.
Supplementary data, including videos, to this article can be found
online at https://doi.org/10.1016/j.jns.2018.02.005.
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