CNS Drugs 1996; 5 Suppl.

I: 1-12
1172-7047/96/OCJJI-ooJI /S06.00/0

© Adis International Umited. All rights reserved .

Extrapyramidal Syndromes
Epidemiology, Pathophysiology and the Diagnostic Dilemma
Daniel E. Casey
Departments of Psychiatry and Neurology, Oregon Health Sciences University, Portland;
Sections of Psychiatry Research and Psychopharmacology, Department of Veterans Affairs,
Medical Center, Portland; and Oregon Regional Primate Center, Beaverton, Oregon, USA

Summary Antipsychotics are the mainstay oftreatment for acute and chronic psychosis,
but these drugs have many troublesome neurological adverse effects. Extra-
pyramidal syndromes (EPS) of akathisia, dystonia and parkinsonism occur in a
majority of patients receiving short and long term antipsychotic therapy. Tardive
dyskinesia occurs in 15 to 20% of patients, but may have a much higher preva-
lence in the elderly. Patient and drug factors strongly influence the risk of the
motor and mental aspects of movement disorders. Dopamine, acetylcholine and
serotonin (5-hydroxytryptamine; 5-HT) receptor antagonism play important roles
in the pathophysiology of EPS. Each EPS has its own unique characteristics that
must be considered in a differential diagnosis. Assessment approaches include a
careful clinical assessment, systematic use of rating scales, and possibly the use
of specialised equipment. Recognition and management of EPS with anti-EPS
medicines or antipsychotic dose adjustments early in treatment will substan-
tially reduce treatment-related adverse effects and improve therapeutic efficacy.

Acute and chronic psychotic symptoms are tipsychotic drug therapies are at risk of developing
most effectively treated by antipsychotic (neuro- disturbances in motor functions)2]
leptic) drugs. Although these compounds have sub- EPS and tardive dyskinesia produce both motor
stantial benefits, they are limited by many adverse (objective) and mental (subjective) symptoms that
effects. Of primary concern are the adverse effects
further burden the al ready impaired psychotic
associated with motor function . These include
patientP-4] Recognition and management of both
acute extrapyramidal syndromes (EPS), wh ich
occur early in treatment (akathisia, dystonia and the motor and mental aspects of these syndromes
parkinsonism), and tardive dyskinesia, which devel- are essential to achieve effective clinical care.
ops much later, during extended drug therapy. When antipsychotic-induced adverse effects are in-
The term 'neuroleptic' was coined in the 1950s tolerable, patients become noncompliant with their
to represent the concept that antipsychotic drugs medicines, increasing the risk of psychotic relapse.
took 'control of the neuron' .[1] As weH as affecting
This chapter will review the epidemiology, risk
psychotic thinking and behaviour, motor dysfunc-
factors and pathophysiological hypotheses of anti-
ti on was recognised as an integral feature of anti-
psychotics. Most antipsychotic drugs produce psychotic-induced dyskinesias. Clinical descrip-
motor function-related adverse effects at doses that tions, differential diagnoses, and strategies for
are close to the effective antipsychotic dose evaluating EPS and tardive dyskinesia will be
threshold. Thus, all patients receiving standard an- discussed.
2 Casey

1. Epidemiology 2. Risk Factors

2.1 Acute EPS

1.1 Acute EPS
2. 1. 1 Patient Variables
The prevalence of acute EPS spans a wide range,
Several patient characteristics, including age,
depending on the specific syndrome as weIl as
gender and history of prior antipsychotic-induced
several patient- and drug-related risk factors. Most
EPS, all influence who will develop antipsychotic-
patients develop single or multiple EPS during the
induced EPS. Akathisia occurs at similar rates in
initial phases of treatment when receiving tradi-
both males and females across all age groups,f4 1In
tional antipsychotics,l21 Furthermore, approxi-
contrast, dystonia is significantly affected by both
mately one-half of all patients on long term drug
age and gender. Dystonia occurs most often in
treatment continue to experience some form ofEPS
young males and is relatively uncommon in elderly
that either limits the dose range of antipsychotics
patients,l2·3.51 Parkinsonism occurs in almost all el-
or causes highly troublesome motor adverse ef-
derly patients at approximately equal rates in both
fects. genders,[3, IO l and there is a relatively high risk for
The average prevalence of akathisia is approxi- adolescents recei ving antipsychotic drugs. [111 If
mately 25%, although the range is 10 to 75%)41
patients experienced EPS from prior antipsychotic
The prevalence of dystonia varies from very low to
treatment, they are at high risk of developing
as high as 90%, depending on the risk factors de-
EPS again if a similar drug type and dose is
scribed below)2.31 Antipsychotic-induced parkin-
represcribed. In this treatment setting, the presence
sonism occurs in approximately 50% of patients
or absence of EPS can be reliably predicted with
receiving these drugS.[2.3 1
75 to 85% accuracy for that patient if the essential
Overall, there has been a steady increase in the drug type and dose data are available.[I2. 131
prevalence of acute EPS over the past several de-
cades. This is undoubtedly due, at least in part, to 2. 1.2 Drug Characteristics
the greater use of higher dosages of high potency, The relationships between parameters of anti-
low milli gram compounds in the 1970s, 1980s and psychotic drug treatment and EPS are complex.
early 1990s. For example, the incidence of dysto- Overall, there is an inverted V-shape curve associ-
nia in the 1950s was 2.3%[51 and it gradually in- ation, where lower doses produce modest EPS,
creased to around 40% in the 1980sPl moderate to high doses produce moderate to high
rates and severity of EPS, and very high or mega-
1.2 Tardive Dyskinesia doses produce fewer EPS than seen with moderate
to high antipsychotic doses.[2,31 One caveat to this
Most studies find a tardive dyskinesia preva- condusion is that there are fewer data available to
lence of 15 to 20%.[6.71 High risk groups such as characterise the side effects of megadoses. Newer
the elderly may have prevalence rates in the 50 to antipsychotic drugs, such as clozapine and risper-
70% range. 17 .81 To accurately account for the true idone, present additional considerations. Clozapine
drug-induced prevalence of tardive dyskinesia, produces fewer acute EPS than other antipsy-
these rates must be corrected or reduced by the rate chotic drugs, although it has some EPS poten-
of clinically similar spontaneously occurring dys- tial (e.g. akathisia),f14- 171Risperidone has a favour-
kinesias. These are present in about 1% of younger able EPS profile, but it is dose related. At lower
people, and up to 5 to 7% of the elderly)61 The doses (I to 6 mg/day), there are far fewer EPS than
incidence of new tardive dyskinesia cases in one at higher doses (6 to 16 mg/day). In recent studies
year is approximately 3 to 5% in younger with risperidone, the higher the risperidone dose
patients,[7.91 but up to 40% in patients > 65 years the greater the number of patients requiring anti-
01d)81 EPS drugs for risperidone-induced EPS.[18- 201

© Adis International Limited. All rights reserved. CNS Drugs 1996: 5 Suppl. 1
Extrapyramidal Syndromes 3

As noted below in the pathophysiology section, drug concentrations,l24,25] Acute dystonic reac-
the relative relationship between dopamine, ace- tions occur most commonly within 12 to 48 hours
tylcholine and serotonin receptor subtype antago- of initiating or rapidly increasing current
ni sm of antipsychotics may play an important role antipsychotic treatment.f3 J Antipsychotic-induced
in their EPS liability. parkinsonism is usually not a prominent problem
When patient, drug and time variables are care- until after several days to weeks of continuous
fully controlled, there is a significant positive rela- treatment. [5J
tionship between increasing blood drug concentra-
tions and EPS.[21.22] In addition, positron emission
2,2 Tardive Dyskinesia
tomography studies show that EPS occur when
more than 80% of dopamine D2 receptors are oc-
cupied by antipsychotics.[23] 2.2. 1 Patient Variables
Concern about EPS is an important factor in se- Increasing age is positively correlated with in-
lecting an antipsychotic drug, although it is not the creasing prevalence and incidence of tardive dys-
sole determinant. Other important adverse effects, kinesia. Approximately 5 to 10% of patients < 40
such as hypotension associated with a-adrenergic years old develop tardive dyskinesia, whereas 50
antagonism, adverse effects on the autonomic to 70% of elderly patients develop tardive dyski-
nervous system, sedation, photosensitivity and nesia from long term antipsychotic therapy.[7]
haematological toxicity (most commonly associ- Women are at a greater risk of tardive dyskinesia
ated with clozapine) must also be considered when than men, at a ratio of approximately 1.7: 1.[7] Af-
choosing an antipsychotic. fective disorders, particularly unipolar depres-
sions, are associated with a greater vulnerability to
2.1.3 Temporal Aspects tardive dyskinesia.l 7,26] Recently non-insulin-
Although any of the disorders can appear during dependent diabetes mellitus (NIDDM) has been
antipsychotic drug therapy, the clinical course of shown to be a risk factor for developing tardive
each EPS has important time characteristics dyskinesia.127.291 This is of particular clinical rele-
(fig. 1). Akathisia may begin within a few hours vance because both tardive dyskinesia and
to a few days of starting antipsychotics;[4] NIDDM have increased risk associated with older
this has been correlated with blood and brain age.

Akathisia Parkinsonism
/ \ ,/ -- . - -. --'-
/ 11\ -- . -

1
/ 1

Dystonia

7 14 30
Time (days)

Fig. 1. The time course 01 acute extrapyramidal syndromes.

© Adls International Limlted. All rights reserved. CNS Drugs 1996: 5 Suppl. I
4 Casey

2.2.2 Drug Factors dopaminergic state, which, at the beginning of anti-

The greater the exposure to antipsychotic drugs psychotic treatment, is caused by an initial dopa-
(total dose and duration of treatment) the greater mine release after a compensatory feedback
the risk ofdeveloping tardive dyskinesia.l7 1All anti- resuIting from postsynaptic dopamine receptor
psychotic drugs, with the exception of clozapine blockadePOl These different hypotheses illustrate
and perhaps risperidone, carry relatively equal risks the significant gaps in our understanding of dopa-
of causing tardive dyskinesia. Depot antipsychot- mine and EPS that fail to adequately explain
ics carry a tardive dyskinesia risk similar to that several observations. 1221
with the orally administered versions ofthese com- The substituted benzamides of sulpiride and
pounds. 171 The minimal number of reports of tard- remoxipride are achallenge to the dopamine hy-
ive dyskinesia induced by clozapine, extending pothesis of EPS. These drugs are highly selective
over several years in many thousands of patients, D 2-receptor antagonists but are associated with un-
indicates that there is a low tardive dyskinesia
expectedly low rates of EPS at doses that produce
potential with this drug. Further research and
antipsychotic efficacy equal to that of haloperi-
more experience will be needed to assess the quan-
dol. 1311 It has been proposed, but not proven, that
titative parameters of tardive dyskinesia risk with
these substituted benzamides may preferentially
risperidone.
antagonise dopamine receptors in limbic or prefron-
There are very few data to indicate that anti-EPS
tal cortical regions while sparing the basal ganglia
drugs such as anticholinergics or antihistaminics D 2 system. [23,311
increase the risk of developing tardive dyskinesia.
The different time course of each EPS and do-
The statistical association that is sometimes seen
pamine receptor blockade is another area of dis-
between anti-EPS drugs and tardive dyskinesia risk
crepancy in the D 2-receptor antagonist hypothesis
is more likely to be due to the fact that EPS is a risk
factor for tardive dyskinesia. 171 Thus, any treatment of EPS. Within 4 to 6 hours of antipsychotic treat-
for EPS, such as anti-EPS drugs, will also show a ment, up to 80% ofD2 receptors can be blocked,f 25 1
statistical, but not necessarily causa!, correlation but not all EPS occur then. The most closely corre-
with tardive dyskinesia. As aseparate consider- lated relationship between dopamine receptor
ation, anticholinergic agents may temporarily in- blockade and EPS on set is with akathisia, which can
crease existing tardive dyskinesia, but symptoms begin within ho urs of drug intake. However, the
return to baseline levels when these drugs are dis- delayed onset of dystonia and even later develop-
continued. ment of parkinsonism after several days of antipsy-
chotic treatment suggest that more complex factors
3. Pathophysiology must be involved beyond the simple explanation of
merely blocking dopamine D 2 receptors.[2,3.23 1
The role of dopamine DI-receptor antagonism
3.1 Acute EPS
in EPS is also complex. Animal models suggest
The pathophysiology of EPS involves a critical that acute DI-receptor antagonism can produce cat-
role for dopamine, a major role for acetylcholine alepsy in rodents and typical EPS in nonhuman
and a hypothetically important role for serotonin. primates.[32-341Yet, with chronic D I-receptor an-
Blockade of dopamine D 2 receptors in the basal tagonism these EPS usually resolve quickly,
ganglia, a property that is common to all effective suggesting tolerance or desensitisation.l33.35-371
antipsychotic drugs, plays a primary role in pro- The role of DI-receptor antagonists in the clinical
ducing EPS. Thus, a reduction in dopamine func- setting remains to be elucidated and extensive clin-
tion (hypodopaminergia) is the most commonly ical trials are required.
proposed mechanism of EPS. An alternative hy- The relative relationships between dopamine re-
pothesis is that acute dystonia is due to a hyper- ceptor subtypes mayaiso play an important role in

© Adis International Limited, All rights reserved. eNS Drugs 1996; 5 Suppl. 1
 Extrapyramidal Syndromes 5

the pathophysiology of EPS. Clozapine, which The theory of dopamine receptor hypersensitivity
probably has the lowest EPS rates, has antagonist has dominated the conceptual approach to under-
activity at dopamine D 1, D2, and D4 receptors.f3 81 standing tardive dyskinesia. This theory proposes
In clinically effective doses that produce few EPS, that dopamine receptors in the basal ganglia be-
clozapine blocks 35 to 65% of D 1 receptors and come functionally overactive as a consequence of
similar rates of D 2 receptors.[23,25] In comparison, long term antipsychotic blockade. However, bio-
traditional antipsychotics, such as haloperidol, chemical evaluations of cerebral spinal fluid and
produce much high er rates of D 2-receptor occu- post mortem studies of dopamine D land D 2 recep-
pancy, which are 80% or greater when EPS are tors have failed to consistently show differences
produced. [23.25] between tardive dyskinesia and nontardive dyski-
Acetylcholine has a major role in mediating nesia groups. Similarly, neuroimaging approaches
EPS, involving a reciprocal balance between dopa- with computerised tomography, positron emission
mine and acetylcholine receptor blockade in the tomography or magnetic resonance have not con-
basal ganglia. This is the basis for the high efficacy sistently identified alesion that can explain tardive
of anticholinergic drugs in reversing or mitigating dyskinesia. Although there is surely a role for long
antipsychotic-induced EPS. This principle also ex- term dopamine receptor blockade by antipsychot-
plains why low milligram, high potency dopamine ics, it may be that dopamine has only a secondary
antagonist compounds, such as haloperidol, which or tertiary, rather than primary, role in the patho-
have little anticholinergic activity, produce more physiology of tardive dyskinesia. Other theories
EPS than the high milligram low potency com- have proposed abnormalities in y-aminobutyric
pounds such as thioridazine, which has consider- acid, free radicals or noradrenergic mechanisms,
ably more intrinsic anticholinergic action. Thus, but there are not sufficient data to either confirm
the greater the dopamine/acetylcholine blockade or refute these hypotheses.l 42 ]
ratio, the greater the likelihood that a drug will
produce EPS.l39] 4. Clinical Descripfion
A more recent hypothesis proposes that a
high ratio of serotonin 5-HT 2 - to dopamine 4.1 Acute EPS
D 2-receptor blockade is an important factor in
The antipsychotic-induced movement disorders
explaining the lower EPS rate with clozapine
that are associated with the initiation of drug ther-
and risperidone.[401 Studies in rodents support
apy are usually thought of as a single group. How-
this hypothesis,f40] but several studies of non-
ever, there are many different clinical aspects to
human primates present a more complex picture
each specific disorder, so they are best considered
of the relationship between serotonin and
as unique entities (table 1).[43 1 Each syndrome has
dopamine antagonism.[41] Additionally, it is un-
a motor and mental component. While the motor
clear if the neurotransmitter relationships apply
characteristics are well known, less attention has
to all EPS, as clozapine and risperidone can cause
been focused on some of the mental aspects of
akathisia at doses that do not cause dystonia or
EPS.
parkinsonism.[14-20]
4. ,. 1 Akafhisia
3.2 Tardive Dyskinesia Subjective distress is the hallmark feature of
akathisia. This syndrome is frequently, but not al-
The pathophysiology of tardive dyskinesia re- ways, accompanied by objective motor signs of the
mains an enigma. Unfortunately, it has not been patient's discomfort (table I). The subjective or
possible to demonstrate with direct evidence any mental aspects of akathisia are often very distress-
consistent abnormalities in the central nervous sys- ing. Intense levels of anxiety, an absence of inter-
tem that can explain the diverse clinical findings. nal calmness, feelings of jitteriness, an inability to

© Adis International Llmlted. All rights reserved. CNS Drugs 1996; 5 Suppl. 1
6 Casey

Table I. Acute extrapyramidal syndromes and tardive dyskinesia (adapted Irom Casey,I431with permission)
Syndrome Motor symptoms Mental symptoms Differential diagnosis Period 01 symptom
onset (days)
Akathisia Pacing, rocking , shifting loot Restless, unable to relax, Severe agitation, psychotic 1·30
toloot poor concentration , irritable decompensation
Dystonia Brielly sustained or lixed Fear, anxiety Manipulation, hysteria, 1·5
abnormal postures 01 the seizures, catatonia
eyes, tongue, lace, neck,
limbs and trunk
Parkinsonism Tremor, rigidity, bradykinesia Bradyphrenia, cognitive Negative symptoms 01 psychosis, 5-30
(akinesia). mask lace, impairment depression
decreased arm swing
Tardive Orofacial, limb and trunk Cognitive impairment, Spontaneous dyskinesias, Years (min:
dyskinesia choreoathetoid dystonic distress stereotypic behaviour > 3 months)
leatures

relax, feeling 'uptight' and difficulty concentrating motor signs of restlessness and have a high level of
are common descriptions of akathisia. The objec- clinical suspicion about akathisia in any patient
tive behavioural motor signs of this subjective dis- receiving antipsychotic medication.
tress are pacing, rocking while sitting or standing,
lifting the feet as if marching in place, crossing and 4. 1.2 Dystonia
Briefly sustained abnormal postures caused by
uncrossing the legs while sitting, frequently
involuntary contractions in opposing flexor and ex-
squirming in achair, or other purposeless repetitive
tensor muscles characterise dystonia (table 1).
actions that often look like the stereotyped behavi-
Symptoms may occur in the head/neck region, with
our associated with psychoses.
eyes deviating to the side or upward (oculogyric
Akathisia was originally defined as subjective
crises), tongue protrusion, jaw spasms (trismus),
distress. Thus, if patients showed motor signs that
tightness or choking feelings in the throat (laryngeal-
were characteristic of akathisia but denied subjec-
pharyngeal constriction) and the head pulling back
tive discomfort, they would not meet the criteria
or to the side (retrocollis, torticollis). Dystonia can
for akathisia but would be described as having
also occur in the trunk and limbs, leading to bizarre
pseudo-akathisia.[44) Although pseudo-akathisia
positions or postures. Dystonia should be given a
has been most often described in association with high index of suspicion when any of these symp-
chronic antipsychotic treatment, it can occur at any toms occur in patients who have recently started
time during this treatment. Since there are no co m- antipsychotic therapy or substantiaBy increased
pelling data to show that patients who demonstrate their antipsychotic dose. Fear of the unknown,
the motor component but deny the mental compo- concern about loss of control of one's muscles,
nent have a different epidemiology, risk factors, and high levels of anxiety in patients may be unde-
pathophysiology or treatment response when com- sirable clinical consequences that are associated
pared with patients with subjective distress, it is with the unpredictable, sudden onset of dystonie
unclear if the distinction between akathisia and symptoms. Psychotic patients with paranoid delu-
pseudo-akathisia has meaningful utility. Even mild sions about external forces controlling them are
forms of fidgeting and restlessness, demonstrated particularly distressed by dystonic reactions. Since
by increased amounts of time walking around that dystonia is a common reason that patients use to
are not associated with subjective distress, may be justify their noncompliance, it is important to pre-
variants of akathisia. Because there may be many vent dystonia with anti-EPS prophylaxis in high
reasons why patients deny subjective distress, it is risk patients or initiate treatment at the first signs
important to give fuB consideration to the observed of dystonia. Mild fluctuating symptoms that can be

© Adis International Limited. All rights reserved. CNS Drugs 1996; 5 Suppl. 1
Extrapyramidal Syndromes 7

overcome with concentration or specific efforts are ment are tardive dystonia and tardive akathisia.
a common feature of the antipsychotic-induced Tardive dystonia is a syndrome of sustained ab-
dystonic syndrome. normal postures or positions that phenomeno-
logically look very similar to acute dystonia.
4.1.3 Parkinsonism
Tardive akathisia is a syndrome of persisting sub-
Tremor, rigidity and/or bradykinesia are the es-
jective or objective signs of restlessness; it is
sential motor features of drug-induced and idio-
phenomenologically similar to acute akathisia.l 441
pathic parkinsonism. Although motor symptoms
Mental components of the tardive syndromes may
are the most prominent feature of parkinsonism,
include distress resulting from not being able to
mental aspects are equally important and can im-
control one's own movements and from the social
pair activities of daily living (table I). Parkinsonian
stigma caused by dyskinesias. Cognitive dysfunc-
tremor is usually a rhythmical 3 to 6 cycles per
tion has also been associated with tardive dyskine-
second to-and-fro motion. It can occur in the ex-
sia, but the causal versus correlational nature re-
tremities, or the head and neck areas. Parkinsonian
mains to be clarified.l491 These tardive syndromes
tremor in the lips has been described as the rabbit
may persist for months and years in some patients
syndrome. [45,461 Rigidity is characterised by
even though antipsychotics are discontinued or re-
ratchet-like or cog-wheel resistance during passive
main at stable doses. Fortunately, for many patients
motion of the limbs. Bradykinesia (slow move-
there is a gradual decrease in and possible remis-
ment), which is also sometimes called akinesia, is
sion of their tardive syndromes over years)6, 501
the reduction in spontaneous motor activity. This
is represented by decreased facial expression, a flat
monotone voice, decreased associated arm swing 5. Differential Diagnosis
during walking, and reduced ability to initiate
movement. Antipsychotic-induced parkinsonism 5.1 Acute EPS
should be diagnosed when any one or more of these
5. 1. 1 Akathisia
symptoms are present (table I). Symptoms may be
Both the motor and mental components of
unilateral, symmetrical, or asymmetrically bilat-
akathisia must be distinguished from psychotic ag-
eral. There are mental components to parkinsonism
itation (table I). Purposeless stereotyped behaviour
that are also disabling. These include decreased
as weil as difficulty concentrating are often prom-
mental activity, bradyphrenia (slow thinking) and
inent features of insufficiently controlled psycho-
cognitive impairment. Patients often experience
ses. In this situation, the appropriate strategy
these subjective parkinsonian features as mental
would be to increase antipsychotic drug therapy.
clouding or as if their mi nd is in a fog.[47, 48 1
However, antipsychotic-induced akathisia can ap-
4.2 Tardive Dyskinesia pear very similar to inadequately controlled psy-
choses but, in this case, increasing antipsychotic
Repetitive, involuntary, hyperkinetic move- doses without concomitant anti-EPS treatment
ments that include chewing, tongue protrusion, could worsen the restlessness and difficulty in con-
vermicular (worm-like) tongue motions, lip centrating. It is critically important to accurately
smacking, puckering and pursing, and paroxysms diagnose and manage akathisia because it can re-
of rapid eye blinking are all features of tardive dys- du ce the potential benefit from antipsychotics.[51 1
kinesia. Choreoathetoid movements in the limbs Other drugs can also cause akathisia. These include
and trunk can also occur. Rarely, tardive dyskinesia the selective serotonin reuptake inhibitor an tide-
involves irregular breathing or swallowing to cause pressants and dopamine antagonists, such as
aerophagia, irregular respiratory rates, belching metoclopramide, amoxapine and prochlorperazine,
and grunting noises)71 Other related tardive syn- wh ich are used for other conditions. Drug with-
dromes associated with chronic antipsychotic treat- drawal from other medications mayaiso lead to

© Adis International Limited. All rights reserved. CNS Drugs 1996: 5 Suppl. 1
8 Casey

pacing, irritability and difficulty in concentrating. for other causes of sustained abnormal postures
Akathisia must be distinguished from acute and should be initiated.
chronic anxiety, which have some ofthe same clin-
5.1.3 Parkinsonism
ical features as this EPS. Restless legs syndrome,
Several different disorders should be considered
wh ich usually occurs when sitting or attempting to
in this differential diagnosis (table I). In older pa-
fall asleep, should also be considered in the
tients, idiopathic parkinsonism may develop. Other
differential diagnosisJ4 1
medical disorders such as hypothyroidism or pro-
5. 1.2 Dystonia gressive supranuclear palsy should be considered.
Manneristic or catatonic behaviour associated Drugs such as metoclopramide or amoxapine,
with insufficiently treated psychoses must be dis- wh ich are dopamine antagonists but are marketed
tinguished from antipsychotic-induced dystonie as a dyspeptic and antidepressant, respectively, can
reactions (table I). Usually the patient's history, produce parkinsonism. l521 Also, depression can
which includes recent treatment details and the produce emotional blunting, cognitive impairment
possibility of drug noncompliance, helps in this and slowed motor function. Positive symptoms of
differential diagnosis. Temporal lobe seizures or psychosis, such as hallucinations, delusions and
space occupying lesions should also be considered paranoia can lead patients to be isolated, secretive,
as possible causes of episodically sustained abnor- withdrawn and emotionally restricted. Similarly,
mal postures. Malingering and hysteria are possi- psychosocial deprivation associated with in-
bilities, although these are less common in psy- stitutionalisation causes many of the same features
chotic patients. Oral or parenteral anticholinergic (fig. 2). Neuroleptic malignant syndrome (NMS)
or antihistaminic agents are usually so effective in should also be in the differential diagnosis of drug-
reversing antipsychotic-induced dystonia that a induced parkinsonism. NMS is characterised by
clinical trial with these agents is usually diagnostic. disturbances in thermoregulation, with fever, as
If the second or third dose of these antidotes does weil as muscular rigidity, frequently an altered
not produce clear clinical improvement, a search level of consciousness and greatly elevated levels

Fig. 2. The differential diagnosis of primary and secondary negative symptoms of psychosis. Abbreviation: EPS =extrapyramidal
syndromes.

© Adis International Limited. All rights reserved. CNS Drugs 1996; 5 Suppl. 1
Extrapyramidal Syndromes 9

of creatine phosphokinase. The hall mark feature of ministered long term to parkinsonism patients.
elevated temperature and severe rigidity, usually Other drugs associated with hyperkinetic dyskinesias
without tremor, distinguishes NMS from drug- incIude oral contraceptives, the chloroquine-based
induced parkinsonism. 1531 antimalarial drugs and stimulants such as amphet-
Negative symptoms ofpsychoses are a critically amines. Hereditary neurodegenerative diseases
important aspect of the parkinsonian differential such as Huntington's chorea and Wilson's disease of
diagnosis (fig. 2). Primary negative symptoms are copper metabolism are to be considered in a differ-
core features of psychosis, whereas drug-induced ential diagnosis. Endocrinopathies such as hyper-
parkinsonism may be a secondary or treatment- thyroidism, hypoparathyroidism and hyperglycaemia
induced cause of symptoms of anergia, emotional are infrequently associated with choreoathetosis.
restriction, avolition and apathy, and psychosocial
withdrawal. Thus, it is essential to make every 6. Assessment Techniques
effort to determine whether the quiet and emo-
tionally resuicted patient is experiencing anti- 6.1 Acute EPS
psychotic-induced EPS adverse effects of brady-
The acute EPS syndromes are all diagnosed on the
kinesia and/or bradyphrenia, or has primary
basis of cIinical presentation and treatment histories.
negative symptoms of psychosis. If the symptoms
There are no uniformly accepted laboratory diagnos-
are part of antipsychotic-induced parkinsonism, it
tic techniques that have achieved wide acceptance for
is appropriate to ameliorate or reverse these symp-
any of these disorders. Each disorder is assessed by
toms with anti-EPS drug therapy or by reducing the
a cIinical examination. This should incIude evaluat-
antipsychotic dose. Decreasing these EPS symp-
ing patients at rest as well as during activation proce-
toms will lead to improved motor and mental func-
dures, which can bring out EPS and other dyskinetic
tioning.l 52J The consequences of misdiagnosing
movements. 154 ,551 Descriptive notations, which may
drug-induced parkinsonism may lead to thera-
be accompanied by standardised rating scales that are
peutic nihilism and a failure to intervene success-
now commonly used to assess antipsychotic-induced
fully with strategies of lower antipsychotic doses,
movement disorders, become part of entries into the
prescribing anti-EPS drugs, or switching to
record. One commonly used scale that encompasses
another antipsychotic.
both the acute EPS and tardive dyskinesia symptoms
is the Saint Hans Dyskinesia Scale,l551 This has been
5.2 Tardive Dyskinesia validated and also has a set of video teaching tapes
for instruction in using the scale and examples of
Abnormal and involuntary movements may
patients with different dyskinetic syndromes. There
have many different causes. These incIude idio-
are also other scales that can be used to assess multi-
pathic syndromes, such as spontaneous hyper-
ple symptoms, such as the Extrapyramidal Symptom
kinetic dyskinesias, which are seen more fre-
Rating Scale l561 and several specific scales tailored to
quently in the elderly and in psychotic patients.
each EPS. Whether one chooses to use rating scales,
Stereotypic and manneristic behaviour is seen in
equipment for objective measuring techniques or
psychotic patients and may appear similar to some
regular cIinical assessments, the most important ele-
symptoms of tardive dyskinesia. Additionally,
ment is that the evaluators develop expertise and con-
Tourette syndrome, simple tics, Sydenham's cho-
sistent reliability in their preferred approach.
rea and dental problems mayaIso cause oral dys-
kinesias. Many other drugs, such as metocIopram- 6.1.1 Akafhisia
ide and amoxapine, can cause dyskinesias,l71 Akathisia rating scales have been recently devel-
Dopamine agonists such as bromocriptine orpergolide, oped to describe and characterise both the mental
or the dopamine precursor levodopa/carbidopa, and motor aspects of this syndrome,l57,581 Careful
also produce hyperkinetic dyskinesias when ad- cIinical descriptions and periodic monitoring will

<D Adis International Limited. All rights reserved. CNS Drugs 1996: 5 Suppl. 1
10 Casey

also provide adequate documentation for manag- niques have been developed for assessing tardive
ing the course of these adverse effects in each pa- dyskinesia, but these are often cumbersome. Two
tient. Electrophysiological methods for assessing more readily applicable approaches include strain
akathisia remain experimental. Such strategies as gauge techniques[60J and equipment using digital
having patients wear activity monitors or stand on image processing.f62J
tilt tables have not been widely applied in clinical
practice. 6.30verview
6. 1.2 Dysfonia
The essential features of good quality assess-
There are no systematically developed or ap-
ments for EPS and tardive dyskinesia are consis-
plied scales for rating antipsychotic-induced dys-
tency and reliability. Whether one chooses to use
tonia. This disorder occurs as a sudden onset syn-
careful clinical assessments, systematically ap-
drome and is probably best characterised by
plied rating sc ales or equipment for objectively
clinical evaluation and a good description in the
measuring dyskinesias, the evaluators must develop
patient's record.
expertise with their preferred approach to ensure
6. 1.3 Parkinsonism that symptom changes will be detected. EPS and
Numerous rating scales have been developed to tardive dyskinesia evaluations should be con-
assess antipsychotic-induced parkinsonism. The ducted each time the mental status is assessed, and
most commonly used is the Neurological Rating whenever antipsychotic treatment is initiated or
Scale, which is generally referred to as the Simpson- changed. Early detection of dyskinesias will lead
Angus Scale.f59J This primarily assesses the motor to timely intervention, appropriate treatment mod-
aspects of parkinsonism; it emphasises the rigidity ifications and enhanced therapeutic outcomes for
component, with a secondary focus on tremor and patients receiving antipsychotic drug therapy.
bradykinesia. The Saint Hans Dyskinesia Scale
gives a more equal rating to the tremor, rigidity and Acknowledgement
bradykinetic phenomena.[551 The mental aspects of
antipsychotic-induced parkinsonism are not yet This work was supported in part by funds from the
Veterans Affairs Research Program, NIMH Grant MH
systematically evaluated with rating scales. The 36657, and core grant RP00l63. The typescript was prepared
tremor phenomenon of parkinsonism can be as- by Crystal Berger.
sessed with accelerometers or other electrophysio-
logical techniques, such as strain gauges, to iden-
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