Parkinson Current Topics
Drug-Induced & Tardive Movement Disorders
by Gwen M. Vernon
Several have postulated that their diagnosis with Parkinson's was preceded by adverse effects from taking different medications earlier in life.
This work is presented for education and research.
Lynn Schmidt-Speed.Section Editor
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.
Questions or comments about this article may be
directed to:-
Gwyn M. Vernon RN.MS, The Graduate Hospital,
Parkinson's Disease and Movement Disorder Center, 1500 Lombard Street, Suite
900, Philadelphia, Pennsylvania 19146. (She is the coordinator).
Copyright American Association 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 patho-physiology 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
sub-acutely, 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 patho-physiology 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 shock-like 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 dopamine
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 ever present 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 efficacy 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
because 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 non-compliance 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
++
Lithium carbonate
++
Caffeine
++
Thyroid hormone
++
Sodium valproate
++
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
+/-
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 well 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)
DA = Dopamine
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: Movement
Disorders: A Comprehensive Survey. Futura Publishing Co., 1989. Reprinted with
permission.
------------------------------------------------------------------------
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, thermo-regulatory 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.
References
1. Ayd Fa: A survey of drug induced extrapyramidal
reactions.
J Am Med Assoc 1961; 175:1054-1060.
2. Caroff SN: The neuroleptic malignant syndrome.
J Clin Psychiatry 1980; 41:79-83.
3. Chase TN, Shur JA, Gordon EK: Cerebrospinal
fluid monoamine catabolites in induced extrapyramidal disorders.
Neuropharmacology 1970; 9:265-275.
4. Faurbye A, Rasch PJ, Peterson PB, et al:
Neurological syndromes in pharmacotherapy of
psychosis.
Acta Psychiatr Scand 1964 40:10-27.
5. Klawans HL: The pathophysiology a drug-induced
movement disorders.
Pages 315-326 in: Parkinson's Disease and Movement
Disorders,
Jankovic J, Tolosa E (editors).
Urban and Schwartzenberg. 1988.
6. Marsden CD: Is tardive dyskinesia a unique
disorder?
Pages 64-71 in: Dyskinesia: Research and Treatment,
Casey DE, Chase TN, Christensen AV. Gerlach J
(editors).
Springer Verlag 1985.
7. Marsden CD, Tarsy D, Baldessarini RJ:
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Pages 219-226 in: Psychiatric Aspects of Neurologic
Disease, Benson DF, Blumer D (editors). Grune and Statton, 1975.
8. Rajput A, Rozdilsky B, Hornykiewicz O et al:
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Clinicopathologic study of two cases. Arch Neurol 1982; 39:644-646.
9. Rajput AH. Offord KP Beard CM et al:
Epidemiology of parkinsonism: Incidence,
classification and mortality.
Ann Neurol 1984; 16:278-282.
10.Singh MM, Kay SR:
A comparative study of haloperidol and
chlorpromazine in terms of clinical effect and therapeutic reversal with
benztropine in schizophrenia. Theoretical implications for potency differences
among neuroleptics. Psychopharmacologia 1975; 43:103-113.
11.Singh MM, Kay SR: A longitudinal therapeutic
comparison between two prototypic neuroleptics (haloperidol and
chlorpromazine) in matched groups of schizophrenics.
Non-therapeutic interactions with trihexyphenidyl.
Therapeutical implications for potency differences.
Psychopharmacologia 1975; 43:115-123.
12.Sweet C: Drug induced dystonia. Am J Psychiatry
1975; 132:532-534.
13.Tolosa E, Alom J: Drug induced dyskinesisas.
Pages 327-347 in: Parkinson's Disease and Movement Disorders,
Jankovic J. Tolosa E (editors). Urban end
Schwartzenberg 1988.
14.Van Praag HM, Ifoif J: Importance of dopamine
metabolism for clinical effects and side effects of neuroleptics.
Am J Psychiatry 1976; 133:1171-1176.
15.Weiner WJ, Lang AE: Movement Disorders: A
Comprehensive Survey.
Futura Publishing Company, Inc., 1989
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Acta Psychiatr Scand 1986; 73:629-633.
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