Extrapyramidal Side Effects and Tardive Dyskinesia. Would You Recognize Them If You See Them?
Anti-emetic, anti-spasmodic and prokinetic medications commonly used in
gastroenterology are neuroleptics, a class of drugs which includes
anti-psychotics used for schizophrenia.
These medications are capable of causing serious and potentially
permanent side effects. The manifestation of neuroleptic drug side
effects may range from dramatic and debilitating to very subtle. It has
been demonstrated repeatedly that these side effects often go
unrecognized.
Doctors prescribing prokinetics, anti-emetics and anti-spasmodics need
to be able to recognize these side effects. A full description of the
most common movement side effects and the corresponding medical term is
included as a resource list for professionals and patients.
BACKGROUND
Any drug capable of causing Extra Pyramidal Side effects (EPS) and
Tardive Dyskinesia (TD) is by definition a neuroleptic, Latin for "seize
the neuron." It is widely assumed that only patients who are being
treated for psychiatric disorders such as schizophrenia are at risk for
neuroleptic side effects, yet several gastroenterology drugs have the
same side effect profile as Thorazine. Patients taking these medications
need to be monitored carefully to prevent potentially irreversible side
effects.
Psychiatrists have long been trained to recognize the signs and symptoms
of EPS and TD and a great deal of physician education has been aimed at
them, yet it has been well documented that they often miss the
symptoms. In some studies, experts in the field pick up twice as many
cases of tardive as newly trained psychiatrists.
Most other physicians have never been trained to recognize the many
different manifestations of EPS and TD. These conditions can be
particularly difficult to recognize in children, even for those with
specific training.
The relationship between neuroleptic medications and movement disorders
is extremely complex and confusing. A neuroleptic may cause movement
symptoms in a patient, but the same drug can also temporarily suppress
the symptoms or delay the onset of symptoms for the same patient.
Symptoms often first appear during withdrawal of the medication.
Movement symptoms can occur spontaneously, but they are often clearly
induced by medication. The best way to avoid permanent movement
disorders is to use neuroleptics very cautiously and to monitor patients
closely for emerging symptoms.
TERMINOLOGY
There are two major classifications of movement disorders, dystonias and
dyskinesias. There are also two time frames used to classify the onset
of symptoms. Dystonias are spasms of individual muscles or groups of
muscles. They can be sustained or intermittent, sudden or slow, painful
or painless. They can affect any of the body's voluntary muscles
including those of the vocal cords. The movements of dystonias can
appear very bizarre and deliberate but are involuntary. Dyskinesias are involuntary, often hyperkinetic movements of various
types that have no purpose and are not fully controllable by the
patient. Some are random, some rhythmic, most are very odd looking and
socially stigmatizing.
They can affect the ability to initiate or stop a movement as in
Parkinson's. They can affect the smooth movement of a joint resulting in
a jerky articulation. Abrupt and seemingly violent movements of a limb
are common as are gyrations of any body part. Tics and involuntary
vocalizations are related to dyskinesias.
Extrapryramidal Side Effects (EPS) describes movement side effects that
begin during the early phases of treatment with a neuroleptic drug.
Early onset symptoms tend to resolve quickly and completely when the
patient is weaned from the offending medication(s). The word refers to
symptoms originating in a specific part of the brain that refines and
modulates movement.
Tardive Dyskinesia/Dystonia (TD) simply means late onset of the same EPS movement side effects.
They can appear after months of trouble free treatment, or they can
begin to appear as the dose is lowered or the drug is withdrawn.
Symptoms generally appear shortly after drug withdrawal although they
can appear months later. The previous cut off of three months post
withdrawal is now being questioned.
Tardive reactions may resolve quickly, but these late reactions are more likely to be persistent or permanent.
Symptoms that persist for six to twelve months are considered to be
permanent although they may diminish slightly over the course of several
years. Masking is the term used to describe the ability of the drug to
cover the toxic symptoms it is producing.
EPIDEMIOLOGY
Studies of movement symptoms in patients taking neuroleptics for
schizophrenia show prevalence rates ranging from .5% to nearly 70%.
Studies examining this wide range of published prevalence rates show the
discrepancies are most likely due to the skill of the observer.
Movement disorders caused by motility and antispasmodic medications in
the treatment of gastrointestinal diseases are widely believed to be
rare.
This assumption is probably dangerous and inaccurate. Small studies of
metaclopramide in particular show EPS and TD in up to 30% of patients.
Given the devastating and potentially permanent nature of TD, extreme
care should be taken to use neuroleptic drugs only when absolutely
necessary and in the lowest doses possible.
RISK FACTORS
Most risk assessment studies on EPS and TD have been conducted in
patients with schizophrenia. In these patients, TD is associated with
older age, higher medication doses and longer treatment periods; i.e.
total exposure. Females also appear to be a higher risk.
Concomitant treatment with any additional drugs capable of causing
neuroleptic side effects is likely to increase the risk of EPS and TD.
This includes both traditional antipsychotics and the newer, "atypical"
antipsychotics which still carry some risk. Substances as common as
alcohol and cold medications have some risk of TD and EPS. Caution is
needed as well with patients taking anticonvulsants, antihistamines,
barbiturates or antidepressants as some drugs in these categories have a
high risk of EPS and TD.
Underlying "soft neurological" factors or mental retardation are significant risk factors in the development of TD.
Many experts caution that tapering down to drug free periods a few times
a year is necessary to ascertain whether a patient has "covert"
symptoms that are being masked by the continuing use of the drug. Other
experts believe that this cycling on and off for "drug holidays" can
provoke a tardive reaction and is an additional risk factor.
RECOGNIZING SIDE EFFECTS OF NEUROLEPTICS
Movement symptoms may be so subtle that a psychiatrist or neurologist
who specializes in movement disorders may be the only expert to pick
them up. But in many unfortunate patients, the symptoms are visible from
blocks away.
Movement symptoms are generally not present during sleep, can worsen with stress,
and patients can often suppress these symptoms for a short period of
time through intense concentration. Movement symptoms may be present
uniformly throughout the day, or they may have a diurnal pattern.
Some specific movement symptoms are more troublesome during resting and
abate during voluntary movement. Other specific symptoms are only
problematic during voluntary movement.
Movement symptoms can wax and wane over time and deliberate provocation
may be necessary to elicit the symptom in a clinical setting. This is
typically done by distracting the patient with conversation or asking
them to perform a mental task, such as math, that requires intense
concentration.
Tongue and facial symptoms are often the first to appear and a thorough
neurological exam involves careful observation of the tongue in the
mouth and sticking out. EPS and TD can mimic disorders such as
Parkinson's Disease, Tourette's Syndrome, Huntington's Chorea, tics, cerebral palsy, stroke and hyperactivity.
They are often mistaken for psychiatric disturbances and patients may be shunned. During episodes of dystonia,
opposing muscles that should relax contract. This can result in a limb
that appears distorted. One of the most common manifestations is an
ankle that twists and won't bear weight. In some cases, muscle groups
that should be uninvolved in the activity being attempted will get
involved. The result can be shoulders that swing violently during
walking or an entire arm and shoulder that cramp and contort while the
hand is holding a pen. In some instances, the opposing hand/arm/shoulder
may also contort in a perverse sympathy.
Some patients find quirky tricks that can short circuit a dystonia or
dyskinesia. For example, a few patients with torticollis find that
stroking their jaw or touching the back of the head can stop the muscle
spasms. A case report describes one patient with a severe gait
disturbance who found that tossing a small object from hand to hand
allowed him to walk more normally. For this reason, patients should be
asked about any odd mannerisms.
In addition to causing movement disorders, neuroleptics used in
gastroenterology are capable of causing a host of other symptoms that
may not be automatically connected with the drug: drooling, autonomic
instability, depression, cognitive slowing, confusion, flat affect, agitation, restlessness, irritability, headaches, disordered thinking, memory changes, altered sensations or perceptions, word retrieval problems, and many others.
Localized Symptoms
Neck/spine symptoms
Associated movement symptoms
Muscle spasms of the neck (cervical) which pull the head to the side
(torticollis), forward and down (antecollis), or up (retrocollis) are
often painful. An extreme bending at the waist is rare (Pisa Syndrome or
pleurothotonus). The most extreme form of back arching can bring the
entire body off the bed except the back of the head and the heels
(opisthotonus). Pelvic rocking or gyrations (axial hyperkinesia) may
appear to be self stimulating or sexual in nature. Jacknifing refers to
abrupt bending at the waist.
Gait/walking disorder
Associated movement symptoms
A disorganized walk (ataxia) may be as subtle as a foot rolling in
occasionally, or as dramatic and absurd as a Monty Python routine. The
patient may appear clumsy, stumbling, clomping or drunk. An inability to
start walking as if glued to the floor and then an inability to stop,
or a shuffling walk are characteristic of tardive Parkinsonism.
Oral facial symptoms
Associated movement symptoms
Oral-mandibular/buccal-lingual symptoms include chewing motions
(sometimes called 'Wrigley Sign'), biting with nose wrinkling ('Rabbit
Syndrome'), tongue probing in the cheek ('Bon Bon Sign'), grimacing,
pouting and repetitive swallowing. The jaw may open or shut or lock
(trismus/lockjaw) making eating difficult. The tongue may protrude
rapidly ('Fly Catcher') or hang flaccidly (tonic). The patient may make
sucking/kissing/smacking/clicking noises. The patient may bite their own
cheeks or tongue. Eyebrows may raise ('Spock eyebrows') or lower making
the person appear haughty or angry. Symptoms confined to the lower face
may be called Miege's Syndrome. Tooth grinding
(bruxism) may occur during sleep. Some symptoms can be aborted by
touching the lips or other tricks. Some patients with tardive
Parkinsonism lack facial expressions (mask-like facies) and they may
drool.
Finger movements
Associated movement symptoms
Finger movements often resemble playing 'Air Guitar', 'Air Piano' or a
particular movement called 'milkmaid grip'. Writer's cramp is a severe
spasm of the entire hand or arm. The opposing arm may also cramp. This
is more than fatigue
and may be induced by fine motor activities other than writing. 'Pill
rolling' finger movements (rubbing the thumb and fingers in a motion
similar to the gesture meaning 'money') are more common in drug-induced
Parkinsonism.
Limb symptoms
Associated movement symptoms
Flailing movements involving a whole limb may appear combative like a
punch or karate kick (ballismus), or may appear like raising a hand to
ask a question. This is one of the few movements that occur during
sleep. Some patients with tardive Parkinsonism have limb movements that
are jerky and have a ratchet-like quality (cog wheel rigidity).
Eye symptoms
Associated movement symptoms
Blinking of both eyelids (blepharospasms) may be so severe that the
patient is legally blind. The eyes may be rolled in any direction
(oculogyric crisis).
Vocalizations, breathing, swallowing
Associated movement symptoms
Vocal tics such as grunting, throat clearing, swearing (coprolalia), and
echoing words or sounds (echolalia) are possible. The vocal cords may
spasm (dysphonia) making the voice choppy, quavery, breathy or cause a
hoarse sounding noise when breathing in (stridor). The vocal cords may
clamp shut (Laryngospasm/obstructive apnea/dysepnea). The speech may be
slurred (dysarthria) or have a quality normally associated with brain
damage (bulbar). Swallowing may be uncoordinated (dysphagia).
MONITORING MOVEMENT SYMPTOMS
The Abnormal Involuntary Movement Scale, (AIMS) is available online and
provides one quick and systematic way to assess a variety of common
movement symptoms. This scale is not useful for distinguishing between
the many types of movement disorders and it cannot distinguish drug
induced symptoms from spontaneous ones. Several other scales are
commonly used and a full discussion of their merits and proper uses can
be found in "Assessment of drug-related movement disorders in
schizophrenia." Since different clusters of symptoms can suggest
different treatments, a full exam by a movement specialist may be
desired.
TREATMENT
Treatment of movement side effects that appear early during treatment
(EPS) is generally accomplished by slowly withdrawing the drug or
lowering the dose.
When the drug is being used to treat a major psychiatric illness such as
schizophrenia, withdrawal of the drug may not be feasible.
Anticholinergic medications may be helpful in EPS, but generally are
not. Beta blockers have also been tried.
Treatment of late onset (TD) movement symptoms and syndromes can be much
more complex. Withdrawal of the drug may need to be undertaken very
slowly and drugs to counteract the symptoms may be tried. Unfortunately,
anticholiergic drugs are generally not as helpful with late onset
symptoms and may occasionally cause paradoxical exacerbation.
Consultation with a movement disorders specialist may be helpful and in
complex cases referral may be necessary.
The long list of drugs that may be used to reduce TD symptoms attests to
the difficulty in treating this iatrogenic disease. Many cases of TD do
not respond well to currently available treatments and there are many
new treatments being investigated including vitamins that act as free
radical scavengers. Vitamin E and vitamin B6 have both shown benefit in
preventing the development of TD although they have not been effective
in treating the disorder once it has developed.
Research is being conducted on the use of branch chain amino acids.
PEDIATRIC CONSIDERATIONS:
Recognition of movement side effects in children is particularly
problematic. Infants are more likely to have boxing arm movements,
cycling leg movements or generalized hypertonia, all of which are
uncommon in adults.
A gait disturbance may not be apparent in a child who is just learning
to walk. Motor restlessness in a pre-schooler can look like urinary
urgency. Early onset EPS or TD can look like cerebral palsy. How do you
distinguish between biting due to a dystonia and a temper tantrum?
Back and neck arching in an infant may be due to pain, an infantile spasm, a seizure, acid reflux
induced Sandifer Syndrome or dystonia. A pediatric movement disorders
specialist may need to examine the child in order to make a definitive
diagnosis.
Non-movement side effects of neuroleptics are also more difficult to
recognize in children. Small children can't tell us that they have a
headache, that they are having memory trouble, that their senses are not
functioning correctly, or that they are suffering from a mood change.
How do you distinguish hormonal changes of puberty from the hormonal
changes (gyncomastia, amenorrhea)
due to prolactin fluctuations caused by a neuroleptic? How do you
distinguish druginduced muscle pain (arthralgia) from the pain of the
disease you are treating? How do you recognize psychosis, dementia or even a sleep disorder in a baby?
There is a wide range of developmental levels within the range of
"normal" making subtle deficits difficult to spot. One author (Anderson)
recently met a toddler who was believed to be profoundly retarded while
on metaclopramide. His "intractable seizures" stopped the day after
withdrawal and he was walking and talking after several months of
intense therapy (personal communications with parents and doctor).
To further complicate matters, children metabolize many drugs
differently. Children have an undeveloped blood-brain barrier which can
leave them more susceptible to CNS involvement where none would be
expected in an adult. Children with acute illness or dehydration seem to be at additional risk for dystonias.
Many common medications can exacerbate neuroleptic side effects. In
addition, pediatric formulations of some drugs contain alcohol which can
exacerbate or precipitate movement symptoms and many other side
effects.
Of particular concern is the alcohol in pediatric ranitidine.
One of the side effects of ranitidine is an interference with the
normal clearance of alcohol that can magnify the effects of the alcohol
by a factor of ten.
Children and the elderly are recognized to be at additional risk of EPS
and TD from neuroleptics used for psychiatric illnesses. It is
reasonable to assume that they are at increased risk when using
neuroleptics for gastrointestinal ailments. The lack of recognition
means that any estimates about the rarity of side effects are suspect. A
few pediatric gastroenterologists no longer use neuroleptics for just
this reason.
LEGAL CONSIDERATIONS
There have been many lawsuits filed by patients experiencing TD. The
Journal of the American Academy of Psychiatry and the Law and the
Journal of Clinical Psychiatry have both printed review articles
describing the many legal issues raised. Acording to "Tardive
Dyskinesia: Tremors in Law and Medicine," most suits have alleged
malpractice but there have also been suits alleging failure to obtain
written informed consent, torts violations, failure to monitor,
inappropriate reassurance that the TD/EPS symptoms were not drug
related, failure to follow standards of care, failure to refer to a
neurologist, product liability, etc.
Institutionalized psychiatric patients have filed suits alleging civil
rights violations. This article is written jointly by a forensic
psychiatrist and an attorney. It summarizes the circumstances, arguments
and rulings from dozens of individual cases and is available online.
"Update on Legal Issues Associated with Tardive Dyskinesia," a section
of a the Journal of Clinical Psychiatry Supplement on TD, contains a
history of the use of neuroleptics and is more medically oriented. It
explains concepts such as determining when the statute of limitations
clock is likely to start in language accessible to doctors.
It gives practical guidelines for physicans who want to avoid lawsuits.
The author explains that, "In determining causation, the law is more
interested in the straw that broke the camel's back than in all the
straws already piled on its back." He includes a quote from a 1984
article; "The impending flood of tardive dyskinesia litigation has
begun. I think that there is an enormous backlog of cases that is going
to plague us for years." He also warns that the pendulum is swinging in
the direction of trying to link all movement disorders to neuroleptics.
Indeed, there are now class action law suits for patients who took metaclopramide and were damaged.
General Symptoms
Akathisia
An inner feeling of restlessness, which compels the patient to pace,
march, fidget or wiggle although some patients are able to sit still. In
infants, this is more likely to look like air boxing or air cycling.
Restlessness may manifest as insomnia. It may be perceived as an uncomfortable inner vibration. Patients may call akathisia anxiety.
Chorea/choreic
Dance-like movements of any body part or the whole body.
Myoclonus/ myoclonic
Involuntary movements that are sudden and violent in appearance as if struck by lightening or hit by an invisible assailant.
Tics
Gilles de la Tourette Syndrome may be drug induced.
Vermicular/ atheoid
Worm-like writhing movement of any body part or the entire body.
Bradykinesia
Slowing of voluntary movements (bradykinesia) can affect any body part
or the whole body. In rare cases there can be a complete lack of
movement (akinesia).
Resting Tremor
Shaking of a resting limb or tongue that tends to subside during
deliberate movements. The opposite of alcohol induced tremors which are
worse during intentional movement.
Neuroleptic Malignant Syndrome
The most dangerous side effect of anti-psychotics is Neuroleptic
Malignant. This Syndrome potentially fatal reaction is characterized by
"lead pipe rigidity," high fever,
dehydration, sweating, elevated blood pressure, fast heart rate and
respiration, agitation, elevated white blood cell count, difficulty
swallowing and autonomic instability.
Paroxysmal
Very abrupt movements
RECOMMENDATIONS
To avoid EPS and potentially irreversible TD, neuroleptics must be used
at the lowest possible doses, for the shortest possible duration, only
when clearly indicated and when there is no safer alternative. Patients
should be monitored closely and frequently for emerging symptoms using
standardized movement rating scales. Possible side effects should be
fully disclosed via written informed consent documents and the doctor
should initiate an ongoing dialog about this topic with the patient. The
doctor should consider alerting family members since they often become
aware of movement disorders before the patient does.
Resources
Journal of Clinical Psychiatry, 2000, Volume 62, Supplement 4, "Update
on Tardive Dyskinesia" contains 9 articles (57 pages) on aspects of TD.
CME credit is available. This supplement includes the article, "Update
on Legal Issues Associated with Tardive Dyskinesia." The supplement may
be ordered on line at
http://www.psychiatrist.com/order.htm
Psychotropic Drug Directory, 2001, Stephen Bazire and William Benfield
Jr., Quay Books, Mark Allen Publishing. This book contains a full list
of drugs capable of causing movement disorders, mood disorders, sleep
disorders, etc., (Chapters 5.8-5.9) with citations for each entry. It
also has a section on the treatment of movement disorders (Chapters
1.20-1.22) with citations to relevant articles for each entry. Order
online at
http://www.markallengroup,com/quaybooks
"Tardive Dyskinesia: Tremors in Law and Medicine," Neil S. Kaye, MD,
FAPA, and Thomas J. Reed Esquire. Journal of the American Academy of
Psychiatry and the Law, 1999; Volume 25, No 2. Viewable online at
http://www.courtpsychiatrist.com/tardive.html
Details of pediatric hypertonia symptoms are available in
"Classification and Definition of Disorders Causing Hypertonia in
Childhood," Pediatrics, 2003: Vol 11, No 1. Available in PDF format
online at
http://pediatrics.aappublications.org/cgi/reprint/111/1/e89.pdf
"Assessment of drug-related movement disorders in schizophrenia,"
Maurice Gervin and R.E. Thomas Barnes Advances in Psychiatric Treatment,
2000; 6: 332-341. This article contains a discussion of several
movement rating scales and reviews methods of conducting them that can
reduce the variability of the results. Available online at
http://apt.rcpsych.org/cgi/content/full/6/5/332
