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Dystonia in parkinson's disease Clinical and pharmacological features.

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Dystonia in Parhnson’s Disease:
Clinical and Pharmacological Features
W. H. Poewe, MD,” A. J. Lees, MD,t and G. M. Stern, M D t
We studied the features of dystonia in 9 patients with untreated idiopathic Parkinson’s disease and in 56 patients on
sustained treatment with L-dopa Dystonia was seen as an initial symptom in patients with both early- and late-onset
Parkinson’s disease and included action dystonia of the limbs and cranial dystonia Although the coexistence of
parkinsonism and dystonia suggests a common pathophysiology, antiparkinsonian drugs did not consistently influence
dystonic spasms. L-dopa-induced dystonia was seen as an off-period, biphasic, or peak-dose phenomenon. Each type
showed a distinctive pattern of localization of dystonic spasms, possibly reflecting neurochemical aspects of basal
ganglia somatotopy. Neuropharmacological studies performed in 12 patients suggest that off-period dystonia is
genuinely induced by L-dopa and best relieved by antiparkinsonian agents.
Poewe WH, Lees AJ, Stern GM. Dystonia in Parkinson’s disease: clinical and
pharmacological features. Ann Neurol 1988;23:73-78
Dystonia as both an initial and a late feature of Parlunson’s disease was recognized almost a century ago E3,
7, 271. It is now most frequently encountered as a
drug-induced phenomenon appearing in the course of
sustained L-dopa treatment [ 151. In this study the clinical characteristics of dystonia in Parkinson’s disease
have been analyzed in 65 patients. Short-term intravenous pharmacological studies were performed in 12
patients with L-dopa-induced foot dystonia to clarify
the underlying neuropharmacological mechanism.
Patients and Methods
All patients with Parkinson’s disease and symptoms of dystonia who attended the Movement Disorder Clinic of University College Hospital between 1983 and 1985 were
studied. There were 9 patients in whom dystonia had been
an initial symptom and 56 in whom dystonia had developed
during L-dopa treatment. In the latter group the average age
at onset of Parkinson’s disease was 48.7 years (range, 24 to
71 years); duration of disease, 9.7 years (range, 2 to 20
years); duration of L-dopa treatment, 8.9 years (range 0.25 to
17 years); and daily dose of L-dopa 654 mg (range, 300 to
2,000 mg). Concomitant drugs were anticholinergics in 22
patients, bromocriptine in 4, and selegiline in 4; 3 had undergone thalamotomy.
Twelve patients were selected for admission to hospital for
short-term pharmacological studies; 10 had L-dopa-induced
early morning foot dystonia, 1 had biphasic hemidystonia
with prominent foot involvement, and 1 showed consistent
exercise-induced foot dystonia (dystonic claudication) unrelated to L-dopa administration.
In all patients with foot dystonia, each episode persisted
From the “University Clinic for Neurology, Innsbruck, Austria, and
the ?Department of Neurology, The Middlesex Hospital, London,
England.
for at least 45 minutes with clear-cut, marked, and painful
dystonic postures. This allowed the immediate responses to
intravenous medications to be assessed reliably. In those with
early morning dystonia, the first daily dose of L-dopa was
withheld for up to 2 hours to ensure reproducible effects; in
the patient with dystonic claudication, tests were carried out
during treadmill exercises. After baseline observations, the
following drugs were given intravenously at a time when
dystonic spasms had reached maximum severity: 75 mg Ldopa, 0.1 mg lisuride (a synthetic ergoline with dopamine
receptor agonist properties), 1 mg haloperidol (a dopamine
receptor antagonist), 5 mg procyclidine (a centrally active
anticholinergic drug), and 1 mg physostigmine (a central inhibitor of acetylcholinesterase). The minimum “washout” period between injections was 24 hours; lisuride challenges
were preceded by 20 mg of domperidone orally 2 hours
before injection. All challenges were performed under single-blind conditions. Responses were assessed by one of us
(W. P.) according to the following scale: (1) complete cessation of dystonia within 30 minutes; (2) marked improvement
of dystonic posturing and pain within 30 minutes; or ( 3 )
marked deterioration of dystonic posturing andor severity of
pain within 30 minutes or increase in duration of the episode. Mild or equivocal responses were recorded as no effect. Speed of response onset was noted, as were changes in
parkinsonian symptoms and the patients self-evaluation.
Results
Dystonia as an Initial Feature of Untreated
Parkinson’s Disease
Of the 9 patients who developed patterns of focal or
segmental dystonia as an initial symptom, in 6 the on-
Received Mar 3, 1987, and in revised form July 15. Accepted for
publication July 15, 1987.
Address correspondence to Dr Poewe, University Clinic for Neurology, Anichstr. 35, A-6020 Innsbruck, Austria.
Copyright 0 1988 by the American Neurological Association
73
set of dystonia preceded other symptoms by up to 13
years; in 3 it concurred with other parkinsonian symptoms.
Writer’s cramp was an initial symptom in 4 patients,
and in 3, exercise-induced painful foot dystonia led to
a distinctive gait disturbance (dystonic claudication); 1
patient with hemiparlunsonism had ipsilateral dystonic
posturing and 2 others had cranial dystonia. In all but 1
of the patients with limb dystonia, Parkinson’s disease
began on the same side. The one exception was a patient who had dystonia of both hands when left-sided
disease appeared.
PATIENT 1. The patient was well until the age of 37, when
she developed dystonic writer’s cramp. Action dystonia of
the right hand soon progressed to involve a variety of manual
tasks, and at the age of 44 blepharospasm and oromandibular
dystonia (Meige syndrome) also became apparent. L-Dopa
(300 mg/day with peripheral decarboxylase inhibitor) led to
worsening of the cranial dystonia and also induced involuntary choreic movements of the right arm. It was replaced by
benthexol (10 mdday), producing modest improvement of
Meige syndrome. The writer’s cramp was replaced by dystonic spasms of the proximal right arm consisting of adduction and pronation, usually triggered by walking. The patient
has been without any medication for the past 3 years and has
gradually developed Parkinson’s disease with right-sided
resting tremor, rigidity, and bradykinesia. Dystonic spasms
of her right arm have stopped but there are still occasional
bouts of cranial dystonia.
Dystonia in L-Dopa-Treated Parkinson’s Disease
Fifty-six patients developed dystonia during sustained
L-dopa treatment; preliminary observations in 42 have
previously been published C261. This group includes 3
in whom dystonia had been an initial symptom, but in
whom the pattern or type of dystonia had markedly
altered after L-dopa had been commenced. Within the
group, in all but 3 recurrence of dystonia was related
to the periodicity of clinical effects of L-dopa and could
be classified as off-period, biphasic, or peak-dose dystonia. Onset of dystonia was related neither to the
duration of Parkinson’s disease nor to the duration of
L-dopa treatment.
Earb Morning and Off-PeriodDystonia
Forty-six of the 56 patients showed dystonia clearly
linked to the L-dopa wearing-off phase. In all but 3,
dystonia tended to occur in the morning before the
first dose of L-dopa had been taken. In 16, it was
succeeded by one or more identical dystonic phases
during wearing-off episodes throughout the day and
night, whereas in 27 it tended to be restricted to the
morning predose phase. In 3, dystonia appeared only
in wearing-off periods in the second half of the day and
74 Annals of Neurology
Vol 23
No 1 January 1988
Painful bilateral dystonicfoot spasms (early morning dystoniaj
in Patient 2. Note bilaterd toe curling with arching of the sole
and inversion at the ankle.
during the night. The clinical pattern was similar in all
46 with off-period dystonia.
PATIENT 2. The patient developed signs of Parkinson’s disease in his right arm at the age of 44 and a year later began
taking 500 mg L-dopa daily with a peripheral decarboxylase
inhibitor. After 6 good years he began to experience end-ofdose effects and predominantly right-sided peak dose chorea;
after 8 years of treatment he developed painful dystonic
spasms of his feet occurring regularly between 6 and 7 AM
before his first dose of L-dopa. During hospital observation,
dystonic cramps were confirmed to begin while the patient
was still in bed with extreme plantar flexion of all toes, arching and inversion of the feet, and marked stiffening and pain
in the calf muscles. Spasms usually started on the left but
gradually became bilateral (Figure). Dystonia could last for
more than an hour while the patient remained severely
bradykinetic and rigid and frequently uttered paranoid ideas
in a barely audible voice. The switch to the on phase about
30 minutes after L-dopa administration was sudden: in less
than a minute his mood would brighten, and dystonic foot
posture resolved to be replaced by right-sided chorea. He
was then able to leave his bed, move freely, and speak
clearly. For the rest of the day he showed wearing-off effects
after each dose of L-dopa, but usually without further dystonic spasms. Early morning dystonia, however, could be
prevented only if he took his first dose of L-dopa at 5 AM.
In the 46 patients with this pattern of dystonia, abnormal postures and painful dystonia primarily affected
the feet and toes with equinovarus deformities and
curling under of toes or extension of the great toe.
Boardlike painful stiffening of the calf muscles on the
affected side was also frequent, but extension of dystonia to involve flexion of the whole leg occurred in
only 5 patients. Involvement of other body segments
in off-period dystonia was also uncommon and when
present it usually affected the homolateral upper limb.
Off-period dystonia was unilateral in 22 patients and
bilateral in 24, of whom 13 showed unilateral predominance.
Off-period foot dystonia tended to involve the side
initially or more severely affected by Parkinson’s disease and was more often present on the same side as
peak-dose chorea.
The duration of individual episodes of off-period
dystonia varied considerably, from iess than 5 minutes
to longer than 2 hours. Wallung or other forms of
exercise involving the lower limbs as well as nervous
tension were triggering factors in 38 patients; rest and
relaxation were generally beneficial. Twenty-three of
43 patients with early morning dystonia experienced
symptoms only after rising.
Biphasic Dystonia
In 7 patients, L-dopa-induced dystonia followed a biphasic pattern with the appearance of dystonic symptoms both during the onset and end-of-dose phases of
an individual dose. In 5 , dystonia was of comparable
severity in both phases; in 2 it was more evident during
the onset-of-dose than in the wearing-off phase. For all
affected patients, onset of dystonia proved to be a reliable indicator that L-dopa peak-dose benefit effects
were imminent. In all patients, biphasic dystonia was
predominantly unilateral, always involving the foot in
an identical manner to that seen in off-period dystonia.
In the majority, dystonia also involved the homolateral
arm and leg; in some there were also signs of cranial
dystonia. The side more affected by biphasic dystonia
was identical to that initially or more severely affected
by Parkinson’s disease in all 7 patients.
3 . The patient developed Parkinson’s disease at
the age of 55 with tremor of the left hand. Four years later
she began L-dopa treatment (4 gm daily) with excellent improvement for 5 years. Response fluctuations then appeared
together with spasm affecting the left lower limb. When the
patient was examined in hospital the following pattern was
seen: upon awaking there was profound early morning
akinesia and bilateral resting tremor of aU limbs. Within 20
minutes of the first dose of L-dopa (500 mg without a decarboxylase inhibitor), her left foot plantar flexed and inverted,
all toes curled under, and the left leg went into painful flexion at the hip and knee for as long as 30 minutes. This
subsided as soon as L-dopa-induced mobility supervened,
permitting movement for the next 90 minutes, after which
identical episodes of limb spasms caused immobility and violent limb tremor to recur. The second dystonic episode also
lasted about 30 minutes until the next L-dopa dose had taken
effect. The rest of the day was dominated by further sequences of biphasic dystonia with a gradual decrease in the
duration of the intervening symptom-free phase.
PATIENT
Three of the patients also had early morning foot dystonia, but the distribution of biphasic dystonia was distinct from off-period dystonia, with more widespread
involvement of the lower h b and trunk.
Peak-Dose-Dystonia
Nine patients had L-dopa-induced dystonic posturing
as peak-dose phenomena. In 2, dystonia was the only
manifestation of L-dopa-induced involuntary movements and both had peak-dose cranial dystonia with
disabling blepharospasm and dystonic jaw spasm. Six
patients with peak-dose dystonic phenomena also had
early morning off-period dystonia; whereas the latter
was always restricted to the lower limb, peak-dose dystonia seemed to be confined to the face and neck in
these patients. In 5, peak-dose involuntary movements
included both facial dystonia and limb chorea.
Pharmacological Observations
Dystonia in Untreated Patients
Six of the 9 patients with dystonia as an initial symptom of Parkinson’s disease were treated with benzhexol at a mean daily dose of 8.6 mg (range, 8 to 12
mg) and 7 with L-dopa (mean dose 400 mg daily in
combination with a decarboxylase inhibitor); only one
patient had taken bromocriptine (total daily dose of 70
mg). Benzhexol treatment led to modest improvement
of cranial dystonia and hemidystonia in 2 patients taking 10 and 12 mg, respectively, but there was worsening of cranial dystonia in 1 patient taking 6 mg, and 6
to 8 mg had no effect on dystonic symptoms in 3. In
contrast to this inconsistent response of dystonia, parkinsonian symptoms showed modest improvement
with anticholinergic therapy in all patients.
Of the 7 patients treated with L-dopa there was an
unequivocal effect on dystonia in 4 leading to marked
deterioration in cranial dystonia (Meige syndrome, 2
patients) and a notable improvement of dystonic claudication and writer’s cramp (1 patient each). In 3,
L-dopa produced no evident effect on dystonia.
Bromocriptine monotherapy was given to only 1 of the
9 patients; both dystonia (writer’s cramp) and parlunsonian symptoms improved.
L-Dopa Withdrawal and Off-PeriodDystonia
In 7 of 46 patients with L-dopa-induced off-period
dystonia, medication was discontinued or reduced by
50% for up to 7 days. All 5 patients who abstained
developed frequent bouts of foot dystonia of increased
duration and severity during the first day of L-dopa
withdrawal; parkinsonian features showed only modest
deterioration. By the end of the second drug-free day,
parkinsonian disabilities had reappeared; foot dystonia
had completely subsided and did not recur until Ldopa was recommenced. Two had been able to estab-
Poewe et al: Dystonia in PD
75
Table I. Foot Dystonia: Pharmacological Challenges ( n
=
12)
No. of Patients Responding
Drug
Dopamiqergic
L-dopa 75 mg IV (n = 110)
Lisuride 0.1 mg IV (n = 10)
Anticholinergic
Procyclidine 5 mg IV (n = 9)
Antidopaminergic
Haloperidol 1 mg IV (n = 10)
Cholinergic
Physostigmine 1 mg IV (n = 9)
Abolition
Improvement
No Effect
Exacerbation
9
6
...
...
6
...
2"
...
...
7"
"Parkinsonian symptoms aggravated.
IV = intravenous.
lish independently a critical dosage of L-dopa below
which they did not experience off-period dystonia
(400 and 500 mg L-dopa per day, respectively).
lntravenotls Challenges in Patients with L-Dopa-lndzlced
Foot Dystonia
The results of challenges with drugs influencing
dopaminergic and cholinergic systems in 12 patients
with L-dopa-induced foot dystonia are summarized in
Table 1. Both dopaminergic agents were effective in
improving foot dystonia. L-dopa was more potent than
lisuride, which had no effect in 2 patients with offperiod foot dystonia and a longer latency before the
onset of benefit (20 to 30 minutes versus 5 to 10
minutes for L-dopa). Procyclidine was also beneficial in
most patients; 2 nonresponders both had off-period
dystonia. Physostigmine exacerbated tremor, rigidity,
and foot dystonia in all but 2 patients. Haloperidol did
not influence dystonia in most patients, but abolished
foot dystonia in 1 patient with early morning symptoms and also in 1 with dose-unrelated dystonic claudication. Some worsening of parkinsonian symptoms followed haloperidol injection in all patients and 2
experienced impairment of L-dopa responsiveness for
more than 48 hours when L-dopa failed to produce the
usual mobility and did not lead to peak-dose chorea.
Discussion
Kmesigenic foot dystonia as an early symptom of Parkinson's disease was described by Purves Stewart E27)
almost a century ago, and there have been a number
of confirmatory recent reports [lo, 12, 14, 183. This
might suggest a shared pathophysiology for dystonia
and bradykinesia, rigidity and tremor. However, in
some patients dystonia becomes less pronounced or
even resolves despite progressive parkinsonism.
The response of dystonia in untreated Parkinson's
disease to antiparhnsonian therapy is inconsistent [10,
12, 181. In this study L-dopa and anticholinergics al76 Annals of Neurology Vol 23 No 1 January 1988
ways improved parkinsonian features, but had unpredictable effects on the dystonic symptoms.
The poor response to L-dopa is an important feature
distinguishing idiopathic Parkinson's disease with dystonia from dystonia-parkinsonism of juvenile onset [2,
331. The latter frequently shows familial occurrence
[2,32} and diurnal variation of symptoms [22,3 1, 321,
suggesting a close relationship to the childhood condition of hereditary progressive dystonia with diurnal
fluctuation (Segawa syndrome) [23, 29, 301. Whether
the difference between dystonia in adult-onset idiopathic Parkinson's disease and the juvenile dystoniaparkinsonism syndromes is due to age-related changes
in the neurochemical organization of the striatum 1247
or reflects a maturational defect of nigral compacta
neurons unique to juvenile dystonia-parkinsonism
1333 is unclear.
Drug-induced dystonia can be classified into offperiod, biphasic, and peak-dose types. Off-period dystonia is by far the most common type of drug-induced
dystonia encountered in Parkinson's disease, with an
overall incidence varying from 20 to 33% of patients
receiving treatment for longer than 3 years [4,213. It
can be regarded as a drug-provoked phenomenon, as it
usually resolves completely when L-dopa is stopped or
the dosage is appreciably reduced, as seen in this and
other studies [9, 193. Furthermore, off-period dystonia
has not yet been observed in patients receiving sustained bromocriptine monotherapy [161.
The mean age at onset of Parkinson's disease in all
three groups with L-dopa-induced dystonia was below
50; in the 7 patients with biphasic dystonia it was below 40. This accords with observations that both offperiod dystonia and biphasic dyskinesia are more common in patients who are younger at onset 11, 9, 20).
One of the most intriguing features of L-dopainduced off-period dystonia is an almost exclusive involvement of the feet-often ipsilateral to the side
most affected by Parkinson's disease-whereas peak-
Table 2. Topography of t-Dopa-Induced Dystonia
in Parkinson’s Disease (n = 56)
Body Area Involved
Foot
Proximal leg
Ipsilateral arm
Trunk
Facetneck
Off-Period
(n = 46)
Biphasic
(n = 7 )
46
5
6
7
5
5
Peak-Dose
9)
(n =
1
1
1
0
1
0
1
4
9
dose dystonia shows a marked predilection for the orofacial region, platysma, and neck. This contrast was
striking in several patients in this study who had dystonic foot postures in the off period and orofacial dystonia when L-dopa had taken effect. Biphasic dystonia
seemed to lie between these poles with marked foot
involvement in all patients but with a tendency to become more widespread (Table 2). Although extension
of off-period dystonia to proximal parts of the limbs
has been seen by others 191, this was only observed in
minor degree in 5 of our 46 patients. Such distinctions
may reflect somatotopic organization within the basal
ganglia, as has been observed in autoradiographic studies of frontoputaminal projections (131 and single cell
recording studies in the putamen and pallidum [ 5 ] of
primates.
The changes in dopaminergic input into the striatum
in Parkinson’s disease have also been shown to affect
the caudate and putamen in a topographically distinct
fashion; the degree of dopamine depletion shows a
rostrocaudal gradient IS}. On the basis of such findings
it is conceivable that involuntary movements triggered
by increased dopaminergic function, i.e., peak-dose
dyskinesias in L-dopa-treated patients, could affect different body areas from those associated with decreased
dopaminergic activity, i.e., off-period dystonia.
It is generally assumed that striatal dopaminergic receptor supersensitivity plays a major role in the genesis
of L-dopa-induced peak-dose dyskinesias [6, 117 and
may also be important in peak-dose dystonia. The
pharmacological mechanism underlying L-dopainduced off-period dystonia, however, is more difficult
to understand. In this study dopamine agonists produced consistent benefit as did the anticholinergic
agent procyclidine; the cholinergic agent physostigmine usually aggravated dystonic symptoms. Accordingly, it has been suggested that dystonic spasms occurring during off periods merely reflect an integral part
of reappearing parkinsonism [lo]. In this study, however, L-dopa withdrawal for more than 24 hours, while
causing reemergence of fully developed parkinsonism,
also led to complete relief from foot dystonia. Similarly, haloperidol aggravated parkinsonism in all patients but did not increase foot spasms and even
improved dystonic symptoms in some patients. Secondary striad cholinergic hyperfunction developing
with sustained L-dopa treatment might be an important
factor in L-dopa-induced off-period dystonia and could
explain the pharmacological findings of this study (251.
However, baclofen and lithium carbonate both may be
of benefit, raising the possibility that other neurotransmitter systems may be involved [17, 21, 287.
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