Movement Disorders
Vol. 8 , No. 1, 1993, pp. 19-27
0 1993 Movement Disorder Society

Phenytoin and Dyskinesias: A Report of Two Cases and
Review of the Literature
M. B. Harrison, G. R. Lyons, and E. R. Landow
Department of Neurology, University of Virginia Health Sciences Center Charlottesville, Virginia

Summary: Dyskinesia is a recognized but uncommon side-effect of treatment
with phenytoin. Two additional cases of dyskinesia during treatment with phenytoin are described; both had radiographically documented thalamic infarctions. The reported experience to date with movement disorders induced by
phenytoin is reviewed and the clinical features summarized. The available
experimental evidence addressing the mechanism underlying this side effect is
side effectsdiscussed. Key Words: Phenytoin-Anticonvulsants-Drugs,
Choreoathetosis-Dy skinesia.

era1 thalamic infarction 1 year prior to this admission, who presented to the emergency room at the
University of Virginia Hospital following a generalized seizure beginning with clonic activity in the
right arm. At the time of presentation he was being
treated for depression on the psychiatric service.
Following his thalamic infarction he had residual
deficits which included a left hemisensory loss, mild
hemiataxia, transient chorea of the left arm and a
chronic pain syndrome. His previous neurologic
evaluation included an angiogram, which revealed
small vessel disease, a 60% left internal carotid artery stenosis and a small right middle cerebral artery aneurysm. Laboratory evaluation included an
extensive rheumatologic workup, which was negative with the exception of an elevated erythrocyte
sedimentation rate of 60 m d h . There was no prior
history of treatment with neuroleptic medications.
At the time of evaluation he was taking amitriptyline and aspirin for his vascular disease. In addition,
there was a remote history of alcohol abuse with
documented abstinence for over 3 years. There was
no family history of neurologic disease.
On physical examination immediately following
the seizure he was confused and agitated. He was
afebrile and blood pressure was 130160. General
physical examination was unremarkable. On mental
status exam he was oriented only to person and did
not follow commands. There were no abnormalities

Since its introduction in 1938 both the therapeutic
efficacy and side-effects of phenytoin have been
well established. The reported neurologic toxicity
includes both acute and chronic effects (1-3). The
cerebellar syndrome of acute toxicity is well recognized and there are reports of irreversible cerebellar
degeneration as well. Encephalopathy , both acute
and chronic, exacerbation of seizures, focal neurologic deficits, ophthalmoplegia (4), and peripheral
neuropathy have all been described. Involuntary
movements are a less familiar complication of treatment with phenytoin and include tremor, asterixis,
myoclonus and dyskinesias. We describe here two
cases of dyskinesia exacerbated by phenytoin,
both of whom had radiographically demonstrable
thalamic lesions. The clinical features are discussed
in the context of a review of the other cases reported in the English language literature.
CASE REPORTS
Case 1
The first patient is a 71-year-old, right-handed
man with a history of hypertension and a right latA videotape segment accompanies this article.
Address correspondence and reprint requests to Dr. Madaline
B. Hamson, Department of Neurology-Box 394, University of
Virginia Health Sciences Center, Charlottesville, VA 22908,
U.S.A.

19

20

M . B . HARRISON ET AL.

on cranial nerve examination. On motor examination there was no evidence of focal weakness. Sensory exam was intact to deep pain. Deep tendon
reflexes showed a left-sided predominance with an
extensor plantar response on the left. Laboratory
evaluations included normal chemistries and CBC,
and negative screen of urine for toxins. Cerebrospinal fluid had a protein of 42 and a glucose of 65.
There were two white cells and no red cells.
After the initial examination in the emergency
room, he had a second seizure and was loaded with
1 g of intravenous phenytoin. The next morning he
was noted to have prominent dyskinesias. These
included marked orofacial dyskinesias consisting
of eyebrow elevation, occasional blepharospasm,
tongue protrusion, and facial grimacing. He also
demonstrated both axial and limb dyskinesia with
frequent side-to-side head movement and occasional truncal rocking, as well as repetitive shoulder
elevation, abduction and extension of arms and
legs, much more pronounced on the left. Distal
choreic movements were less frequent. His phenytoin level was 14.3 mg/L. The dyskinesias resolved
over 3 days coincident with a decrease in the phenytoin level to less than 2.5 mg/L. His mental status
returned to baseline within 24 h of admission. An
MRI (Fig. 1) showed the old right thalamic infarction and was unchanged. An EEG revealed left temporal spikes. Seizures were treated with valproate
because of a prior history of allergy to carbamazepine, used to treat his thalamic pain syndrome,
and development of a rash in hospital while treated
with phenobarbital, On follow-up evaluation he has
remained stable with no recurrence of choreic dyskinesias.

Case 2
The second patient is a 60-year-old, right-handed
woman admitted 3 months prior to our evaluation
with new onset dysarthria and right hemiparesis.
On admission she was noted to be lethargic with
dysarthria, right facial weakness and right hemiparesis involving both arm and leg. She had rightsided hyperreflexia but no sensory deficits. Past
medical history was remarkable for hypertension,
stage three adenocarcinoma of the ovaries resected
in 1985 and two prior cerebral aneurysms clipped in
1963 and 1983 at another hospital.
Her hospital course was complicated by persistent lethargy, which cleared after several days. She
continued to demonstrate mild weakness greater in

Movement Disorders, Vol. 8 , N o . 1. 1993

FIG. 1. Case I . The MRI shows the previous infarction in the
right thalamus, with probable involvement of the subthalamic
nucleus or connections to it. Diffuse white matter disease and
infarctions in the right internal capsule and caudate and left putamen are also present.

the arm than in the leg. Lumbar puncture was refused. Other evaluation included a CT scan (Fig. 2),
which showed subacute infarction on the left involving the internal capsule and thalamus. An EEG
showed suppression of background activity over
the left hemisphere and independent bitemporal
sharp waves. Phenytoin was begun with a level
prior to discharge of 14.7 mg/L on a dose of 300
mg/day. Although not noted by the medical staff,
the patient and her husband reported the onset of
involuntary right hand movements before discharge.
Following discharge, because of dysphagia, she
was changed to phenytoin elixir at the same dose.
On medical follow-up she was found to have a phenytoin level of 36 mg/L. She was ataxic, but otherwise asymptomatic, and her phenytoin dose was
reduced to 150 mg/day. When she returned for follow-up 2 months after her infarction, some adventitious movements were noted in her right hand.
These were interpreted as possible seizure activity
and her dosage was increased to 200 mglday. She
returned 1 month later complaining of more abnormal movements of the right hand interfering with

21

PHENYTOIN A N D DYSKINESIAS
DISCUSSION
Clinical Features

FIG. 2. Case 2. This CT scan shows a subacute infarction in the
left thalamus.

use of the hand. At that time she was noted to have
right-sided facial weakness and a high-pitched dysphonic voice without dysarthria. She had spasticity
and mild weakness of the right arm. Deep tendon
reflexes were increased in the right arm but were
otherwise normal. The most prominent feature of
her exam was repetitive, irregular, nonrhythmic
flexion and extension movements at the right wrist
and in the digits of her right hand. These were
present at rest and with action and were increased
with sustained posture. She was noted to have tapping of her right foot, which was asynchronous with
the arm movements. Her gait was normal with the
exception of accentuation of her dyskinesia; she developed more pronounced finger movements and
proximal extension of dyskinesia to the shoulder.
Her phenytoin level was 21.8 mg/L and her medication was held. Five days later, the phenytoin level
was 5.1 mg/L and the movements were unchanged.
One month subsequent to discontinuing the medication the movements had significantly improved
although they had not completely resolved. When
seen 3 months after phenytoin was stopped, the involuntary movements had decreased further, occurring only intermittently during her exam and no
longer producing functional impairment.

Dyskinesias induced by phenytoin represent an
uncommon but recognized complication of phenytoin therapy. Seventy-seven cases have previously
been reported in the English literature including
four from German authors that have been described
in review articles in sufficient detail to be included
here. In 1950 there was a case report of acute toxicity secondary to phenytoin overdose in which
“generalized tremors” were described (5), but the
first case report in which choreoathetotic movements were clearly noted was in a 1962 (6) abstract
with a full report published in 1966 (7). A 1963 article from the psychiatric literature described toxic
psychosis, choreoathetosis, and truncal dystonia
accompanying phenytoin toxicity (8). There have
been multiple subsequent reports of dyskinesias
during treatment with phenytoin (9-46). The cumulative experience with this entity and its clinical features are reviewed below, focusing on the dyskinesidhyperkinesia syndrome. Tremor, asterixis, and
myoclonus have been reported; these are less specific abnormalities, being seen in a wide range of
metabolic and toxic disturbances.
The demographic distribution of the 77 cases is
shown in Table 1 . The age range is from 10 months
to 81 years with the majority of cases occurring in
younger individuals. Over 50% of the reported
cases occurred in patients less than 20 years of age
with only 20% in patients over 40. This age distribution may actually reflect epidemiologic features
of epilepsy and/or phenytoin use. In addition, there
TABLE 1. Demographic distribution
Age (range: 10 mos-81 yrs)
0-10
1 1-20

21-30
3140
41-50
51-60
61-70
>70
NS

27
13
12
9
1
6
3
3
3

(35%)
(17%)
(15%)
(12%)
(1%)
(8%)
(4%)
(4%)
(4%)

43
33
1

(56%)
(43%)
(1%)

Sex

Male
Female
NS
mos, months; yrs, years.

Movement Disorders, Vol. 8, N o . I , 1993

22

M . B . HARRISON ET AL.

is a slight male preponderance with males representing 56% of the cases and females 43%. Our
cases fall within the older end of the spectrum with
only six previous cases (8%) reported in patients
over the age of 60 (17,18,24,31,32,45).
Pharmacologic features of the previously reported cases are shown in Table 2. At the time the
dyskinesias occurred, 32% of the patients were taking phenytoin alone while 68% were on two or more
anticonvulsant drugs. Levels were measured in the
majority of patients, and only 7% had levels of less
than 10 mg/L. Four of these were children, one of
whom was taking valproic acid concurrently
(36,37). The other patient was an adult male with
prior tardive dyskinesia that recurred on treatment
with phenytoin and with quite low total levels (27).
Twenty-three percent of the patients had total levels within the standard therapeutic range of 10-20
mg/L. In five of these patients the free levels were
measured (36,45,46). It was at the expected fraction
of 10% in one patient and elevated in four, three of
whom were obstetrical patients with low serum albumin concentrations. In 57% of the previously reported cases the level was in the toxic range of
greater than 21 mg/L. In 13%, drug level was not
specified.
Use of more than one anticonvulsant may contribute to development of this side-effect by increasing free levels. Both phenobarbital and valproic acid, which were the most commonly combined
medications, can increase the relative free fraction
of phenytoin in the serum. It should also be noted
that an identical clinical picture has occasionally
been described during monotherapy with both carbamazepine (47-49) and phenobarbital (25,50,5 1). A
case was also reported in which abnormal movements occurred after the addition of ethosuximide
to phenytoin and subsided when the ethosuximide
was withdrawn (52).
In prior case reports the determination of the

TABLE 2. Pharmacologic factors
Treatment regimen
Phenytoin alone
3Two AED’s
Phenytoin level (mg/L)
<10
10-20
221
NS

Single IV infusion

AED, antiepileptic drugs.

Movement Disorders, Vol. 8. N o . 1, 1993

25
52

(32%)
(68%)

5
18
44
10
14

(7%)
(23%)
(57%)
(13%)
(18%)

drug responsible has been made on the basis of an
increased level, timing of the dyskinesias in response to introduction of the drug or increase in
dosage and the response to withdrawal and/or rechallenge. With respect to our Case 1 it is of interest
that 18% of the reported cases occurred after a single intravenous infusion. This may relate to the
pharmacokinetics of the medication in which peak
levels occur quite rapidly following an intravenous
infusion (26). As the dyskinesia can persist in the
face of falling drug levels, a single high peak in susceptible individuals may be sufficient to provoke
the dyskinetic response.
The frequency of specific dyskinesias in the previously reported cases are shown in Table 3. The
dyskinesias described represent a spectrum of hyperkinetic movement disorders. Frequently the patients described demonstrated more than one type
of dyskinesia. Analysis of true frequency is hampered by the limited clinical data in many reports as
well as inconsistency in the use of descriptive
terms. Choreoathetosis was the most common manifestation, being present in 91% of the previously
reported cases. Orofacial dyskinesia, which was
quite prominent in our Case 1 , has been seen in
67%, generally in connection with choreoathetosis.
There are only three cases reported previously in
which orofacial dyskinesias were seen in the absence of choreoathetosis and in one of those patients there was a concurrent neck dystonia (18,31).
Dystonia has been reported in 23% of the patients,
but in only three cases did the dystonia occur in the
absence of another movement disorder (18,35,38).
Ballism has been less commonly reported, being described in only 7% of the patients. In only one patient was it the sole manifestation. This was a 28year-old man with a history of alcohol dependence
in whom ballism was described as affecting only the
lower extremities (29).
Another feature that has been considerably discussed in the literature is that of predisposing factors. These are shown in Table 4. The most commonly reported predisposing factor is static encephalopathy or mental retardation, described in 39% of
the patients. Thirteen percent were reported to
TABLE 3. Type of dyskinesia
Choreoathetosis
Orofacial dyskinesia
Dystonia
Ballism

70
49
18
5

(91%)
(67%)
(23%)
(7%)

PHENYTOIN AND D YSKINESZAS
TABLE 4. Predisposing factors
Static encephalopathy
Prior dyskinesias
Structural lesion
Neuroleptic treatment
Miscellaneous

30
10
9
4
5

(39%)
(13%)
(12%)
(5%)
(7%)

have had prior dyskinesias, two with a past history
of Sydenham’s chorea (31,38) one with tardive dyskinesia (27), and one who had previously received a
diagnosis of senile chorea (31). Our clinical experience suggests that preexisting movement disorders
may be underreported or undiagnosed and this figure may underestimate the true frequency of this
predisposing factor. Neuroleptic treatment was a
predisposing factor in only 5% of the cases. Three
patients had been previously treated with neuroleptics and one, as mentioned, was already known to
have tardive dyskinesia (13,27,32). In one patient
the concurrent administration of phenytoin with a
neuroleptic was the pharmacologic setting in which
the dyskinesia occurred (32). There were miscellaneous causes identified as possible predisposing
factors in five cases or 7%. One of these was a
patient who had had a cardiopulmonary arrest (18),
one was a patient with neurofibromatosis (25), one
patient was documented to have abnormal metabolism of phenytoin (lo), and one had abnormal copper metabolism (6). In the fifth case, both the seizures and abnormal movements occurred in the setting of meningoencephalitis (44).
In only 12% of the previously reported patients
was a focal structural lesion identified. This was
often not clearly related to the development of dyskinesia. One case description reports postmortem
findings consistent with multiple lacunes in the striatum bilaterally (24). In another case, calcification
in the globus pallidus was reported (36). The other
structural lesions reported were left frontal abscess
(18), residual shrapnel in the frontal lobe (23), a
history of severe head trauma (37), a probable mass
lesion with findings of midline shift on pneumoencephalography and angiography (17), a previously
resected meningioma (32), parasagittal glioblastoma
(41), and history of an old subdural hematoma (26).
The two cases reported here represent the only two
with radiographically documented thalamic lesions
in spite of association of such lesions with both chorea (53) and oral dyskinesias (54). However, exacerbation of unilateral asterixis secondary to thalamic lesions by phenytoin treatment has been re-

23

ported (55). Our cases demonstrate recurrence
(Case 1) and exacerbation (Case 2) of unilateral chorea secondary to thalamic infarction by the administration of phenytoin; in Case 1 the additional basal
ganglia lesions may have contributed to the more
generalized features.
Pathophysiology
In spite of the wealth of clinical observations regarding the potential of phenytoin to induce dyskinesias, there is little understanding of the mechanism of this effect. Phenytoin has been shown to
accumulate in brain tissue. In experimental work in
an overdose model in the cat, there was regional
variability with higher levels in the cerebellum and
basal ganglia than in the cortex (56). In human tissue examined after temporal lobe resection, levels
in brain tissue were 4-10 times those in spinal fluid
or serum (57). It has been established both in human
tissue and animals, that phenytoin binding is not
receptor mediated and appears to be nonspecifically
bound to proteins and/or phospholipids (57,58).
An extensive literature exists on the pharmacologic effects of phenytoin on neurons in multiple
preparations (59-62). At therapeutic concentrations, it has been shown to block sustained repetitive firing via an effect on sodium channels and this
is believed to be the primary mechanism underlying
its anticonvulsant effect. At supertherapeutic concentrations it has been shown to decrease both calcium influx into the neuron and transmitter release.
This may be relevant even at therapeutic levels in
view of the finding of a preferential concentration in
neuronal tissue over and above the levels observed
in the serum. It has also been shown to inhibit calcium and calmodulin regulated protein phosphorylation, which carries with it the potential for an impact on second messenger systems. The effects on
chloride conductance have been variable in different studies. Both positive and negative effects on
chloride conductance have been found. Under depolarizing conditions phenytoin also prevents increase of cyclic AMP. The interaction of phenytoin
with various neurotransmitter systems in the brain
has been examined as well. It has been shown to
increase the concentration of gamma-amino-butyric
acid (GABA). Variable effects have been reported
on acetylcholine. While phenytoin has been shown
to decrease the activity of acetylcholinesterase (63),
there is a dose dependent effect on release with low
doses stimulating and higher doses inhibiting acetylcholine release (62).

Movement Disorders, Vol. 8 , No. I , 1993

24

M . B . HARRISON ET AL.

The pharmacologic system within the brain of
greatest relevance to the dyskinetic side-effects is
the dopaminergic system. Because of the clinical
observations, the interactions of phenytoin with dopaminergic systems in the brain have been examined experimentally. The effects are summarized in
Table 5. Because of the similarities of the clinical
features to tardive dyskinesia, particularly the
prominence of the orofacial dyskinesia, an initial
hypothesis was that phenytoin produced this effect
via a blockade of the D2 receptors, a mechanism
similar to the action of neuroleptics. No studies
have examined this directly by looking at inhibition
of binding. However, effects on dopamine metabolism have been examined.
In the striatal slice preparation, phenytoin inhibits the uptake of tritiated dopamine, which is an
active transport process occurring in the presynaptic dopaminergic terminals (64). Phenytoin has been
found to have variable effects on dopamine metabolite levels. It has been shown to inhibit the monoamine oxidase system responsible for breakdown of
dopamine in brain tissue (62). However, in the CSF
of patients treated with phenytoin, an increased
level of homovanillic acid (HVA), one of the degradation products of dopamine has been found (65).
There was no change seen in the levels of either
HVA or DOPAC (3,4-dihydroxyphenylaceticacid)
in the rat brain after administration of phenytoin
(66). The significance of the finding in humans is not
clear. The possible mechanisms would include both
increased turnover and decreased reuptake or decreased transport from the CSF.
Several studies have examined the effects of phenytoin administration on dopamine mediated behaviors. In the naive rat there was either no change
or a decrease found in apomorphine-induced stereoTABLE 5. Inteructions with the dopaminergic system
Effects on dopamine metabolism:
Inhibits [3H]-dopamine uptake in slices
Variable effects on dopamine metabolite levels
Effects on dopamine mediated behaviors:
No change or decrease in apomorphine induced stereotypy
in naive rat
Increases behavioral supersensitivity to apomorphine after
pretreatment with neuroleptics
Decreases turning induced by apomorphine after 6-OHDA
lesion
Behavioral effects of phenytoin administration:
Acute: catalepsy
Chronic: after withdrawal, motor activity increases and
there is a delayed increase in apomorphine induced
stereotypy

Movement Disorders, Vol. 8, N o . I , 1993

typy (31,66,67). In animals pretreated with neuroleptics, behavioral supersensitivity to apomorphine
was actually increased by phenytoin administration
(31,68). However, after dopamine denervation in
the 6-hydroxydopamine (6-OHDA) lesion model,
phenytoin administration decreased the turning induced by apomorphine, which is another indicator
of behavioral supersensitivity (66,69). In studies of
the effects of acute administration, phenytoin produced catalepsy similar to that produced by administration of dopamine antagonists (67). In studies
looking at chronic phenytoin administration and
then withdrawal, motor activity increased after cessation of phenytoin treatment (67) and a delayed
increase was seen in apomorphine-induced stereotypy (70).
To summarize, in models believed to represent
supersensitivity, possibly at the level of the dopamine receptor, contradictory effects were found
with a potentiation of supersensitivity after neuroleptic treatment but an inhibitory effect on apomorphine turning after a 6-OHDA lesion. It is interesting to consider these results in light of what is
known about the effects of a 6-OHDA lesion on the
interaction of the D1 and D2 subtypes of the dopamine receptor. In the normal rat, actions at the Dl
and D2 receptor are synergistic and stimulation of
both subtypes is required to produce dopaminemediated behaviors. Conversely, treatment with either D1 or D2 antagonists can block these behaviors. In the 6-OHDA lesion model, dopamine denervation functionally uncouples the D1 and D2
receptor, so that stimulation at either receptor with
a specific agonist can produce the full range of effects and treatment with one antagonist alone is not
sufficient to block them. In the normal animal given
a drug acting at both D1 and D2 receptors, there
was little, if any, effect of phenytoin. In the setting
of uniform dopamine depletion after a 6-OHDA lesion, an inhibitory effect on the expected increased
response to a mixed dopamine agonist was seen,
whereas in the setting of chronic blockade of one
subset of the dopamine receptor, the D2 receptor,
the dopamine agonist effects were potentiated. It
may be that phenytoin’s mechanism of action preferentially affects one subtype of the dopamine receptor or mimics its effects. This recalls the observation that phenytoin decreases the level of cyclic
AMP in brain tissue, an effect which has also been
reported through action at the D2 receptor.
The balance of the experimental evidence indicates that phenytoin can affect dopamine mediated

25

PHENYTOIN AND D YSKZNESZAS

behaviors although the mechanism remains unclear.
This is supported by some clinical observations that
are of interest in this context. There have been reports of decreased responsiveness to levodopa in
patients with Parkinson’s disease who received
phenytoin therapy (69). In addition, there are two
case reports in which a parkinsonian syndrome was
induced after treatment with phenytoin, one in a
child (71) and one in an adult (72). It has been
known for some time that phenytoin can worsen the
chorea in Huntington’s disease (69). As we have
seen in both of the cases presented here and those
previously reported, it can either induce or worsen
other hyperkinetic syndromes.
In summary, phenytoin-induced dyskinesias represent a well-documented complication of treatment. Though there is some clustering of occurrence at earlier ages, it can occur at any age during
either chronic or initial treatment. It is more common in the face of an increased drug level and if it is
suspected, free levels should be checked. This increase can be transient as in the setting of intravenous loading. It is more commonly seen with polytherapy with two or more anticonvulsants. The
movement disorder is variable but usually consists
of a generalized choreoathetosis with or without
orofacial dyskinesias. A similar syndrome has been
described less commonly with other anticonvulsants and should be suspected in that setting as
well. Although the specific mechanism is unknown,
we hypothesize that there is disturbance in the functional equilibrium of the basal ganglia output systems, perhaps due to a differential effect of phenytoin on dopamine receptor subtypes or their associated second messenger systems. There is evidence
that vulnerability to this effect is increased in the
abnormal CNS. The cases presented here represent
the only two with radiographic evidence of a structural lesion of the thalamus and involvement of the
connections to the subthalamic nuclei is most likely
implicated as an underlying abnormality.
Acknowledgment:We would like to thank G . Frederick
Wooten, M.D., for critical review and Rose Powell for
manuscript preparation.

LEGENDS TO VIDEOTAPE

Segment 1. This patient is a 71-year-old man
with a previous right thalamic infarction (Case 1).
He is shown the day after receiving 1,000 mg of
phenytoin intravenously. Initially, he is at rest with

few adventitious movements; his dyskinesia is
markedly activated when he begins to speak. He
demonstrates axial dyskinesia involving neck and
trunk and large amplitude proximal movements of
the extremities, left more than right, resulting in
limb displacement, as well as less frequent distal
choreic movements. The prominent orofacial dyskinesias are demonstrated in the following portion.
These include eyebrow elevation, occasional blepharospasm, tongue protrusion, and facial grimacing;
the adventitious movements interfere with his attempt to sustain tongue protrusion. In the last two
scenes, the patient is shown following discontinuation of phenytoin and resolution of the acute dyskinesia. Occasional movements of the left arm are
seen as he describes his prior dyskinesia.
Segment 2. This patient is a 60-year-old
woman with a previous left thalamic infarction
(Case 2). She is shown at the time of initial evaluation 3 months after her infarction while receiving
phenytoin. The abnormal movements shown are restricted to the right upper extremity and consist of
repetitive irregular flexion and extension of the
wrist and fingers. These are accentuated by use of
the arm and by walking.
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