Several have postulated that their diagnosis with Parkinson's was
preceeded by adverse effects from taking different medications earlier
in life.
This work that is presented for education and research.
Lynn Schmidt-Speed. Section Editor
Since knowledge of pharmacology is important to neuroscience
nurses. Pharmacology Update is presented as a regular feature.
Drug-induced movement disorders are discussed in this issue.
Drug-induced and Tardive Movement Disorders
Gwyn M. Vernon
Questions or comments about this article may be directed to Gwyn
M. Vernon, RN. MS at The Graduste Hospital Parkinson's Disease
and Movement Disorder Center 1500 Lombard Street, Suite 900
Philadelphia, Pennsylvania 19146. She is the coordinstor.
Copyright American Asssociation of Neuroscience Nurses 0047
2603/91/2303-0153 $1.25
J Neuroscience Nursing 1991; 23(3):183-187.
Introduction
Drug-induced movement disorders and tardive syndromes present a
unique challenge for neuroscience practitioners. Our
understanding of the pathophysiology of these iatrogenic
problems has developed mainly through clinical observations,
while treatment and prognosis in most cases are complex and less
than optimal. This article discusses drug-induced and tardive
movement disorders, risk factors, management and nursing
implications.
Causative Agents
Movement disorders secondary to pharmacological agents
represent a large number of extrapyramidal disorders seen by
neurologists and psychiatrists in the outpatient setting.
Involuntary movements, including tremor, chorea, athetosis,
dyskinesias, dystonia, myoclonus, tics, ballismus and akathisia,
may be symptoms of primary neurologic disease or occur secondary
to pharmacotherapy (Table 1). Drug-induced abnormal movement
syndromes have been recognized since the 1950s, following the
introduction of chlorpromazine (Thorazine) to treat
schizophrenia.
The risk of developing a drug-induced movement disorder begins
at the onset of treatment with an offending agent. Drug-induced
syndromes may develop acutely, within hours or a few days, or
subacutely, over several weeks. Yet others may develop after
prolonged exposure to an offending agent. When a movement
disorder develops six months or longer after exposure, the term
"tardive" is used, implying a late or delayed onset.
Most of our understanding of the pathophysiology of movement
disorders has developed from clinical observations of response
to pharmacotherapy.[5] Tardive syndromes appear to originate
from drug effects on the striatal dopaminergic system. Five
classes of drugs are known to affect central dopaminergic
systems:[5,15]
-------------------------------------------------------------------
Table 1
Movement Characteristics
Tremor Rhythmic. oscillatory movement categorized
according to its relationship to activity or
posture
Chorea Irregular, unpredictable brief jerky movements
Athetosis Slow, writhing movements of distal parts of
limbs
Dyskinesias Recessive abnormal involuntary movements
Dystonia Slow sustained, posturing or contractions of a
muscle or group of muscles
Myoclonus Rapid, brief shocklike muscle jerks
Tic Repetitive. irregular stereotype movements or
vocalizations
Bellismus Wild flinging or throwing movements
Akathisia Subjective sensation of restlessness often
associated with inability to keep still. Easily
confused with psychiatric symptoms such as
agitation, hyperactivity and anxiety
-----------------------------------------------------------
* Central stimulants that act as indirect dopainine
agonists such as amphetamine
* Levodopa, a precursor of dopamine
* Direct dopamine agonists such as bromocriptine
* Presynaptic dopamine antagonists (dopamine depleting
agents) such as reserpine
* Neuroleptics such as haloperidol (Haldol) or
chlorpromazine (Thorazine), and other medications such as
metoclopramide (Reglan) which antagonize or block central
dopamine receptors
By far, the most common cause of drug-induced and tardive
syndromes are those that block or antagonize dopamine receptors,
usually the neuroleptics.
Prognosis for the patient with a drug-induced movement disorder
ranges from complete recovery to chronic, persistent movements,
often resistant to therapy. Tragically, many patients develop
these syndromes after insufficient consideration of the
everpresent danger of this adverse effect. Neuroleptics and
other drugs known to commonly cause movement disorders (Table 2)
should be used cautiously and reserved for situations where the
benefits outweigh the risks. Even then, short-term therapy of
minimal therapeutic dosages should he the strategy employed.
While drug-induced and tardive syndromes can present with any of
the involuntary movements, parkinsonism, dyskinesias and
dystonia tend to be the most common.
Parkinsonian
Drug-induced and tardive parkinsonism resemble idiopathic
parkinsonism, and are therefore characterized by tremor,
rigidity and most commonly an extreme paucity of movement called
akinesia. Ironically, tardive parkinsonism was recognized as a
reserpine induced akinesia prior to our understanding of the
importance of dopamine deficiency to the manifestations of
idiopathic parkinsonism. Today, neuroleptic induced parkinsonism
is the second leading cause of parkinsonism symptomatology
following idiopathic Parkinson's disease.[9]
The mechanism of tardive parkinsonism appears to be the
drug-induced opposition or blockade of striatal dopamine
receptors. This results in a subsequent imbalance in the normal
acetylcholine-dopamine relationship.[5]
While parkinsonism may begin within several days of treatment,
it usually follows a more delayed or subacute onset with 90% of
cases evidenced within three months.[1] Women appear to have a
higher incidence than men. Overall the incidence of developing a
drug-induced parkinsonism ranges from 5-60% depending on the
type of neuroleptic employed.[7] Drug-induced parkinsonism
appears dependent on two variables, drug type and dosage. The
relative dopamine receptor blocking activity varies between
offending agents, however all patients have the potential for
developing tardive parkinsonism if dosages are continually
escalated.[15] Additionally, research supports the hypothesis
there may be subclinical deficits in the dopaminergic system
related to normal aging or even preclinical Parkinson's disease
which may contribute a significant risk for developing tardive
parkinsonism.[1,8]
When drug-induced parkinsonism occurs, the offending medication
should be reduced, withdrawn or changed to an agent with a lower
propensity for causing this adverse effect. However, this plan
is not always feasible because of the underlying psychiatric or
medical illness. Anticholinergics, or more commonly, amantadine
(Symmetrel) are used to treat symptoms in cases where drug
reduction, withdrawal or alternative therapy fail. Routine use
of anticholinergics in patients receiving neuroleptics is not
suggested as prophylaxis as there is evidence anticholinergics
may reduce therapeutic efficscy of neuroleptics.[11] Moreover,
adverse effects of anticholinergics such as hallucinations and
confusion may exacerbate underlying psychiatric symptoms.
Tardive Dyskinesia
Following the introduction of chlorpromazine (Thorazine) in
1952, several researchers began to describe a complicated
movement disorder following exposure to this drug. Lipsmacking,
facial and lingual masticatory movements, trunk rocking and
restless foot movements were some of the movements described.
Faurbye and his colleagues coined the term tardive dyskinesia
and described it as a syndrome of abnormal movements following
at least six months and often many years of neuroleptic therapy,
hence, tardive or late onset.[4] Today, tardive dyskinesia is
characterized by choreiform movements of the mouth, tongue,
face, arms, legs and body, in order of decreasing frequency.[15]
Risk factors for developing tardive dyskinesia include:
* chronic neuroleptic therapy especially polypharmacy
* age greater than 40 years
* chronic schizophrenia
* institutionalization
Females are more commonly affected than males.
Institutionalization is included as a risk factor becausc of
long-term, high dose neuroleptic therapy frequently employed in
chronic care facilities. Indiscriminate use of anticholinergics
may also increase a patient's risk for developing tardive
dyskinesia by blocking the cholinergic system and thereby
enhancing dopamine hence creating a neurotransmitter imbalance.
Onset of tardive dyskinesia may be insidious or emerge as
neuroleptics are being reduced or discontinued. This pattern
theoretically is related to denervation-hypersensitivity
phenomenon. It appears with prolonged receptor blockade by a
neuroleptic, the receptors rebound, becoming supersensitized.
Medication noncompliance such as running out of a prescription
or undergoing sudden drug withdrawals and resumptions are a
common cause of this denervation-hypersensitivity rebound
phenomenon.
The best treatment for tardive dyskinesia is prevention. The
indication for long-term neuroleptics must be well established
and continually re-evaluated, with alternatives considered. Once
tardive dyskinesia presents, a gradual reduction of the
neuroleptic should be attempted in hopes of a spontaneous
remission. Overall 60% of persons may improve, however it may
take two or more years for a remission to occur.[6] Drug
interventions for persistent dyskinesias include low doses of
benzodiazepines, dopamine antagonists and other dopamine
depleting agents such as reserpine and tetrabenazine.
Frequently, patients prefer the neuroleptic be resumed as the
effectiveness of other agents is often insufficient to bring a
satisfactory level of relief from the abnormal involuntary
movements. At best, the prognosis for patients with tardive
dyskinesia is poor. Emphasis must be placed on prevention,
appropriate use of antipsychotics and early recognition of this
phenomenon.
------------------------------------------------------------
Table 2
Syndrome Drugs responsible
-----------------------------------------------------------
Postural tremor Sympathomimetica ++
Levodopa ++
Amphetamines ++
Bronchodilators ++
Tricyclic antidepressants ++
Lithium carbonate ++
Caffeine ++
Thyroid hormone ++
Sodium valproate ++
APDs (1) ++
Hypoglycemic agent ++
Anrenocorticosteroids ++
Alcohol withdrawal ++
Amiodarone +
Cyclosporin A +
Others
Acute dystonic APDs ++
reactions Metoclopramid ++
Antimalarials +
Tetrabenazin +/-
Diphenhydramine +/-
Mefenamic acid +/-
Oxatomide +/-
Flunarizine and cinnarizine +/-
Akathisia APDs ++
Metoclopramid ++
Reserpine ++
Tetrabenazine +
Levodopa & DA agonists (3,4) +
Flunarizine and cinnarizine +/-
Ethosuximide +/-
Methysergide +/-
Parkinsonism APDs ++
Metoclopramide ++
Reserpine ++
Tetrabenazine +
Alphamethyldopa +
Flunarizine and cinnarizine +/-
Lithium +/-
Phenytonin +/-
Captopril +/-
Alcohol withdrawal +
MPTP (2) +
Other toxins (Mn, Carbon disulfide
cyanide) +
Cytosine arabinoside +/-
Chorea,including APDs ++
tardive Metoclopramide ++
dyskinesis and Levodopa ++
orofacial Direct DA agonists (3) ++
dyskinesia Indirect DA Agoniets and other
Catecholaminergic Drugs (4) ++
Anticholinergics +
Antihistaminics +
Oral Contraceptives +
Phenytonin (T) +
Carbamazepine (T) +/-
Ethosuximide +/-
Phenobarbital (T) +/-
Lithium (T) +/-
Benzodiazepines +/-
MAO Inhibitors +/-
Tricyclic antidepressants +/-
Methyldopa +/-
Methadone +/-
Digoxin +/-
Alcohol withdrawal +/-
Toluene (glue) snifling +/-
Flunarizine and cinnarizine +/-
Dystonia, APDs ++
including Metoclopramide ++
tardive Levodopa ++
dystonia Direct DA agonists (3) +
(excluding acute Phenytoin (T) +
dystonic Carbamazepine (T) +/-
reactions) Flunarizine and cinnarizine +/-
Neuroleptic APDs +
malignant Tetrabenazine + AMPT +/-
syndrome Withdrawal of antiparkinsonian
drugs in Parkinson's disease +/-
Tics (simple and Levodopa +
complex), Direct PA agonists +
including Indirect PA agonists ++
aggravation of APDs +
pre-existing tic Carbamazepine +/-
disorders
Myoclonus Levodopa (T) ++
Anticonvulsants (5) (T) ++
Tricyclic antidepressants ++
APDs +/-
Others (6)
Asterixis Anticonvulsants (5) (T) ++
Levodopa +/-
Hepatotoxins (T) ++
Respiratory Depressants (T) ++
Others (6) (T) ++
++=Well documented common or not infrequent
+=Relatively we11 documented; uncommon
+/-=Not well documented or only sma11 number of cases in
literature
T=Usually other evidence of drug toxicity present
(including serum drug levels)
1. APDs=antipsychotic drugs
2. MPTP=1-lMNethyl-4-Phenyl-1,2,3,6-Tetrahydropyridine
3. Includes: Apomorphine, Bromocriptine, Lisuride,
Pergolide, Others
4. Includes: Amphetamines, Methylphenidate, Amantadine,
Pemoline, Fenfluramine, Nomifensine
5. Includes most categories of anticonvulsant drugs
6. Includes wide variety of other drugs capable of causing
toxic encephalopathy
From Weiner WJ, Lang AE. Pages 600-602 in: Movement Disorders:
A Comprehensive Survey. Futura Publishing Co., 1989. Reprinted
with permission.
Editors note: The abbreviation DA in this table is used to
denote dopamine.
------------------------------------------------------------------------
Tardive Dystonia
Tardive dystonia, resembling idiopathic torsion dystonia, is
characterized by contorting posture(s) of a muscle or muscle
groups. Tardive dystonia commonly affects the face or neck, but
may also involve the leg or trunk. Other drug-induced movement
disorders including tardive dyskinesia, akathisia (a subjective
sensation of restlessness) or myoclonus may accompany tardive
dystonia, and have led many researchers to classify tardive
dystonia as a variant of tardive dyskinesia, Unlike tardive
dyskinesia, tardive dystonia is seen in children as well as
adults. As many as 2% of psychiatric inpatients have been noted
to have features of tardive dystonia.[16]
There are no known biochemical changes in idiopathic dystonia,
however, it has been postulated through pharmacologic
observation an alteration may exist in the cholinergic system.
Clinically, patients with tardive dystonia often respond to
dopamine-depleting drugs or antagonists. However, if
ineffective, patients should be offered trials of the
pharmacological therapy used in patients with primary idiopathic
dystonia.
Infrequent Drug-Induced Syndromes
Two other syndromes, although infrequently seen, warrant
consideration because of their potential morbidity and
mortality: acute dystonic reactions and neuroleptic malignant
syndrome.
Acute dystonic reactions have been associated with all
neuroleptics. Swett found an incidence of acute dystonic
reactions in 10.1% of patients studied on a variety of
antipsychotic drugs; males under the age of 30 were most
commonly affected.[12] Acute dystonic reactions are frequently
seen in the psychiatric setting, or bring patients in the
community to the emergency room within hours or a few days after
the initiation of therapy with a neuroleptic, metoclopramide
(Reglan) or other potential drugs. Like idiopathic and tardive
dystonia, the pathophysiology of acute dystonic reactions
remains obscure.
Treatment for acute dystonic reactions includes withdrawal of
the offending agent and parenteral infusion of an
anticholinergic or antihistamine such as benztropine (Cogentin)
or diphenhydramine (Benadryl) followed by oral anticholinergic
therapy every 4-6 hours for the next 24-48 hours.
Neuroleptic malignant syndrome is the least common of the
extrapyramidal adverse effects of neuroleptic drugs, but the
most dangerous.[2] Idiosyncratic reactions including fever,
severe rigidity, tremor, autonomic instability and obtundation
lead to pulmonary embolism, myocardial infarction and
disseminated intravascular coagulation. Death occurs in 20-80%
of the cases while gradual spontaneous resolution over 2 weeks
occurs in the remainder.[15] Infrequently, patients continue to
exhibit involuntary movements including dyskinesia or
parkinsonism upon recovery from the acute phase.
The pathological mechanism of neuroleptic malignant syndrome is
uncertain, however, it is thought the neuroleptic blocking
effects on striatal dopamine receptors result in severe rigidity
and excessive heat production from severe muscle contraction.
Additionally, thermoregulatory function maybe altered by central
effects of the neuroleptics.
Life supporting care including provision of fluids and
electrolytes, cooling and artificial ventilation may be
required. Dopamine agonists and direct acting skeletal muscle
relaxants such as dantrolene sodium have been used with fair to
good results.[2]
Nursing Implications
Nurses in many settings are exposed to patients at risk for, or
who suffer from drug-induced and tardive syndromes. Prevention
of these complications is the best treatment. Careful assessment
of the need for antipsychotic treatment must be considered along
with knowledge of the risk of a persistent, irreversible
involuntary movement disorder evolving as a complication of
neuroleptic therapy. Nurses are in a position to carefully
discuss these risks and benefits with the medical team, patient
and family. Constant weekly monitoring for early detection of
abnormal involuntary movements is an important role of the
nurse. Education of the patient and family is of utmost
importance, with emphasis placed on the goals of treatment,
medication effects and potential adverse effects. Compliance
should be monitored and patients must be discouraged from sudden
drug discontinuance, Additionally, comprehensive care including
options such as day programs and counseling should be considered
to assist in resolving or optimally managing psychiatric
problems. Once a movement disorder develops, nurses must
carefully monitor the patient, assess therapeutic alternatives
and provide reassurance and counseling for the patient and
family.
Summary
Drug-induced and tardive movement disorders represent a large
number of extrapyramidal disorders seen in neurologic practice.
Iatrogenically induced, most commonly by neuroleptics, these
disorders can be characterized by any abnormal body movement
including tremor, chorea, athetosis, dyskinesias, dystonia,
myoclonus, tics, ballismus or akathisia. Parkinsonism,
dyskinesias and dystonia tend to be the most common. Management
of patients with drug-induced or tardive syndromes is complex.
Prognosis is frequently poor as patients usually need the
offending agent to manage their underlying psychiatric or
medical problem. Neuroleptics and other drugs known commonly to
cause movement disorders should be used cautiously and
significant consideration of all risks and benefits measured
before initiating therapy.
Acknow1edgment
The author wishes to thank Matthew B. Stern, MD, for useful
comments in support of this article, and Rita Verrilli for her
assistance in the preparation of the manuscript.
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