ORIGINAL CONTRIBUTION

Dopaminergic Dysfunction in Midbrain Dystonia
Anatomoclinical Study Using 3-Dimensional Magnetic Resonance Imaging
and Fluorodopa F 18 Positron Emission Tomography
Marie Vidailhet, MD; Corinne Dupel, MD; Stéphane Lehéricy, MD, PhD; Philippe Remy, MD, PhD;
Didier Dormont, MD; Michel Serdaru, MD; Pierre Jedynak, MD; Hugues Veber, MD;
Yves Samson, MD; Claude Marsault, MD; Yves Agid, MD, PhD

Objective: To determine the role of damage to neuronal

systems,especiallythedopaminergicsystem,inpatientswith
symptomatic dystonia and mesencephalic lesions.
Design: Stereotaxic magnetic resonance imaging analysis and positron emission tomography after the administration of fluorodopa F 18.
Patients: Of a group of 48 patients with unilateral dys-

tonia following a stroke, 7 patients with a well-defined
midbrain lesion were selected.
Results: All patients had unilateral dystonic posture of
an upper extremity and cerebellar dysmetria or hypotonia. Cerebellar tremor was present in 1 patient. Two patients had resting and postural tremor, which showed a
marked improvement with treatment with levodopa. In
patients with dystonia only, dopaminergic lesions were
mostly confined to the ventromesial mesencephalon and

red nucleus area, including the substantia nigra and nigrostriatal and cerebellothalamic fibers. Dystonia was severe and did not resolve with time in patients with lesions involving the nigrostriatal pathway, and the degree
of dopaminergic denervation revealed by positron emission tomography was correlated with the severity of dystonia. In patients with resting and postural tremor, lesions of the dopaminergic structures were larger and
located more laterally and dorsally in the pars compacta, the perirubral and retrorubral areas, and extending to the central tegmental tract.
Conclusions: Dopaminergic dysfunction plays a role in

the occurrence and severity of midbrain dystonia, and
additional lesions to dopaminergic neurons in the perirubral and retrorubral areas result in tremor that responds
to levodopa treatment.
Arch Neurol. 1999;56:982-989

L

From The French Institute of
Health and Medical Research
INSERM U289 (Drs Vidailhet,
Lehéricy, and Agid) and the
Departments of Neurology
(Drs Vidailhet, Serdaru,
Jedynak, Veber, and Agid) and
Neuroradiology (Drs Lehéricy,
Dormont, and Marsault),
Hôpital de la Pitié-Salpêtrière,
Paris; and the Service
Hospitalier Frédéric Joliot
(Drs Dupel, Remy, and
Samson), Commissariat à
l’Energie Atomique, Orsay,
France. Dr Vidailhet is now
with the Department of
Neurology, Hôpital Saint
Antoine, Paris.

ESIONS AFFECTING the striatopallidal complex and thalamus are responsible for most
cases of symptomatic focal
dystonia.1-3 Dystonia may occasionally be caused by midbrain lesions4,5 affecting the dopaminergic nigrostriatal system, the red nucleus area, and
the superior cerebellar peduncle.6,7 In patients with a midbrain lesion, dystonia is
frequently associated with tremor,1 which
usually responds to treatment with levodopa.7 That dopaminergic cell loss has
a role in the cause of resting and postural
tremor has been suggested both experimentally8,9 and clinically.7,10 In contrast, it
is unclear whether midbrain structures contribute to dystonia, with or without tremor.
We used stereotaxic analysis of 3-dimensional (3-D) T1-weighted magnetic
resonance imaging (MRI) and positron
emission tomographic (PET) examination with fluorodopa F 18 ([18F]) to investigate which structures are responsible for
dystonia that occurs alone or with tremor.

RESULTS

ILLUSTRATIVE CASES
Patient 4
A 56-year-old man with a medical history of diabetes mellitus and hypercholesterolemia had a stroke at age 55 years.
For 2 to 3 days, he had dizziness, gait
ataxia, and diplopia. At that time, the patient had a complete left third nerve palsy,
mild cerebellar ataxia on the tandemwalk test, cerebellar dysmetria, and adiadochokinesis of the right arm. No sensory loss was detected. Two days after the
stroke, dystonia was observed. At the time
of the study, he had mild dystonic posture with hyperextension and abduction
of the fingers of the right hand on action.
When he walked, internal rotation of the
arm and flexion of the wrist and the fingers associated with dystonic hyperextension of the big toe were present. The dystonia score was 6. An MRI showed a left

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PATIENTS AND METHODS
PATIENTS
Patients were selected for this study if they had both unilateral, localized symptomatic dystonia and the presence
of a well-defined lesion due to a midbrain stroke. Of 48 patients with unilateral poststroke dystonia observed in our
department between 1989 and 1997, 7 fulfilled the criteria. The clinical features and topography of the dystonia
and associated movement disorders and the cause of the
stroke are summarized in Table 1. Dystonia was defined
as sustained muscle contractions that caused twisting and
repetitive movements or abnormal postures. 11 Polygraphic electromyographic recordings and accelerometry
measurements were obtained in all patients with associated tremor (Table 1). The clinical assessment and polygraphic electromyographic recordings were made blind to
the 3-D MRI analysis of the anatomical location of the lesion. Dystonia was evaluated using the Fahn and Marsden
scale,12 and akinesia and rigidity tremor were evaluated with
the scores on the motor subscales of the Unified Parkinson’s Disease Rating Scale.13 The baseline score was obtained 12 hours after a patient had withdrawn from antiparkinsonian treatment. The treated score was measured
when the patient had attained maximal improvement of motor signs. The dystonia score is the sum of the scores for
each part of the body of the provoking factor (0 indicates
no dystonia; 4, dystonia present at rest) 3 the severity factor (0 indicates no dystonia; 4, dystonia present most of
the time). Maximal possible score is 120.
MRI EXAMINATION
All studies were performed on a 1.5-T MRI unit. After a scout
sequence was taken, the following 3 series of scans were made
at each examination: sagittal, T1-weighted; coronal, 3-D Fourier-transform spoiled-gradient acquisition at the steady state,
T1-weighted (1.5-mm slice thickness); and axial or coronal,
T2-weighted. Compared with computed tomographic scans
or standard MRI, 3-D T1-weighted MRI sections present several advantages: thin sections (1.5 mm), reducing partial voluming; multiplanar analysis; and reformatted images.
STEREOTAXIC LOCALIZATION OF THE LESIONS
The stereotaxic procedures were conducted with the 3-D Fourier-transform spoiled-gradient acquisition sequence, using a Voxtool software workstation system (Advantage Windows Workstation; General Electric Co, Milwaukee, Wis).

paramedian midbrain infarct (Figure 2, B). The results
of echocardiography and cerebral angiography were normal. The patient was treated with aspirin (250 mg/d). One
year after the study, the patient’s condition improved, and
he considered himself normal. Dystonia was observed only
when he walked.
Patient 5
A 63-year-old man with a medical history of cardiac infarct and heavy smoking had a first transient ischemic

Images were reformatted sections, independent of the subject’s head position, and were strictly symmetrical in the axial,
sagittal, or coronal planes. Axial and sagittal sections were
reconstructed parallel to the axis of the anterior and posterior commissures, and coronal reconstructions perpendicular to the axis of the anterior and posterior commissures were
performed (contiguous 1-mm-thick slices). The line of the
anterior and posterior commissures was superimposed on
each slice (determined as the shortest distance between opposing surfaces of the commissures). These reconstructions allowed the calculation of the coordinates of length,
height, and laterality of the lesions compared with the bicommissural line. Measurements were corrected for the width
of the third ventricle, the height of the thalamus, and the
length of the line of the anterior and posterior commissures. These coordinates were analyzed according to the atlas of Hassler. The 3-D MRI analysis of the lesions was made
blind to the clinical assessment.
POSITRON EMISSION TOMOGRAPHY
All patients were examined using a high-resolution brain PET
scanner (ECAT 953B/31; CTI, Knoxville, Tenn) that collects 31 simultaneous 5-mm-thick planes, 3.38 mm apart, with
an in-plane resolution of 6 mm.14 None of the patients was
taking dopaminergic medication at the time of the PET study.
Benserazide, a peripheral blocker of the dopa decarboxylase, was given in a dose of 50 mg 1 hour before tracer was
administered. The patients were positioned and maintained
using an individually molded head holder. The correction for
tissue attenuation of 511-keV gamma radiation was measured. Scanning was initiated immediately after the intravenous administration of [18F]fluorodopa, 130 to 333 MBq. Nine
time frames were acquired in the ensuing 90 minutes.15,16
The time frames collected from 30 to 90 minutes were
summed to create an integrated image such as the one presented in Figure 1. Circular regions of interest (ROIs; diameter = 10 mm) were placed by visual inspection above the
head of the caudate nucleus (1 ROI) and the putamen (3
ROIs) in each plane where these structures were visible.15,16
A circular ROI was placed on the occipital region at the
same level. Regional time-activity curves were obtained, and
[18F]fluorodopa uptake constants (Ki per minute) were determined in the caudate nucleus and the putamen using a
multiple-time graphic analysis and the occipital activity as
a nonspecific input function.15,17,18 The results obtained in
the patients were compared with the Ki values measured using the same methods in the caudate nucleus and the putamen of 11 control subjects (age, 36 ± 6 [mean ± SD] years)
and 13 patients (age, 59 ± 8 years) having severe Parkinson
disease (stages IV-V on the Hoehn and Yahr scale).15

stroke at age 53 years. Clinical signs, including clumsiness, left arm paresthesia, diplopia, and dysarthria, persisted for several hours. At age 54 years, he had right
hemiplegia plus coma. A computed tomographic scan
showed an old infarct of the right middle cerebral artery
(perisylvian cortical region) associated with a recent infarct of the vertebrobasilar system involving the left temporo-occipital region of the posterior cerebral artery, the
bilateral paramedian thalamic, and the left midbrain. Echocardiography showed apical cardiac hypokinesia. Cerebral angiography did not show significant arterial steno-

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Table 1. Clinical Characteristics of the Patients*
Patient No.

Sex
Age at onset of
dystonia, y
Duration of
dystonia, y
Initial signs at
onset of stroke

1

2

3

4

5

6

7

M
39

F
66

F
51

M
55

M
54

M
17

M
55

12

11⁄2

3

1

9

24

0.5

Right hemiparesia,
aphasia

Drowsiness,
Right third nerve
dysarthria,
palsy, left
ataxia, left
cerebellar signs,
cerebellar
pyramidal signs
signs, Parinaud
syndrome
Unknown
Unknown
3 mo
,1 wk

Left third nerve
palsy, right
cerebellar
signs

Cause of the stroke Cardiac embolism
Unknown
Interval between
2 mo
,1 wk
stroke and onset
of dystonia
Site of onset of
Right hand
Left hand
Left hand
Right hand
dystonia
Type of dystonia
Extension, abduction Forced extension Forced extension of Extension of the
of fingers,
or flexion of the the fifth finger,
fingers,
pronation of the
fifth finger
flexion of the other pronation of
arm, dystonic
(transient)
fingers
the arm,
smile
extension of
the big toe
Associated
Mild parkinsonian
Bilateral mild
Absent
Absent
movement
rigidity
parkinsonian
disorders
rigidity,
akinesia

Neurological signs Very mild,
during the study
hemiparesis,
hypopallesthesia
Dystonia score at
12
time of PET scan
Evolutions of
Spread to the face
dystonia

Ataxia, left
Very mild cerebellar
cerebellar
signs in the left
signs, Parinaud arm
syndrome
1
1

Mild cerebellar
signs in the
right arm

Disappeared

Improved

Disappeared

6

Paresthesia of the Coma, left
right arm,
hemiparesia
cerebellar signs,
diplopia

Right cerebellar
signs,
vestibular
syndrome

Unknown
5 mo

Trauma
,1 y

Cardiac embolism
11⁄2 mo

Right hand

Left hand

Right hand

Forced extension
of the fingers

Forced extension
of the fingers

Forced extension
of the fifth
finger
(transient)

Cerebellar
Rest tremor (4 Hz), Rest tremor,
proximal
irregular postural irregular
postural tremor, tremor in the
tremor (5.5 Hz),
right arm and
proximal action
proximal action
thigh
tremor, mild
tremor, mild
rigidity, akinesia
rigidity, akinesia
Mild cerebellar
Mild cerebellar
Mild cerebellar
signs in the
signs in the
signs in the
right arm, mild
left arm
right arm, mild
hypoallesthesia
hypoesthesia
6
9
1
Stable

Stable

Disappeared

*PET indicates positron emission tomography.

Control

Patient 5
2.0

0.5

[18F]Fluorodopa

Figure 1. Positron emission tomographic (PET) scan in a healthy control
subject (left) and in patient 5, who had a left mesencephalic lesion. The
images correspond to the integration of PET images acquired 30 to 90
minutes after the administration of fluorodopa F 18. The right side of the
brain is shown on the left. All images are normalized to their mean occipital
values (eg, occipital activity = 1).

sis. The patient was treated with warfarin. The patient’s
hemiparesis resolved completely. Six months after the
stroke, the patient complained of tremor in his right arm.
Intermittent resting tremor was observed in the right hand

(flexor digitorum, with little involvement of the extensor digitorum) and arm (largely in the biceps). On polygraphic recordings, bursts of tremor (145-200 milliseconds) were separated by silent periods, and alternating
agonist-antagonist tremor was observed. Tremor was clinically similar to parkinsonian tremor, although the mean
frequency was 4.0 to 4.5 Hz on accelerometry. When the
arms were extended, the frequency increased to 5.5 Hz,
and tremor became less regular. During voluntary movements, tremor increased greatly in amplitude.
Nine years later, at the time of the study, the results of polygraphic recordings were unchanged. Magnetic resonance imaging showed a left thalamomesencephalic infarct (Figure 2, C). Slow, regular resting tremor
was observed in the right arm. Postural and action tremor
of great amplitude was present. A dystonic posture with
extension of the fifth digit of the right hand was observed in all positions. The dystonia score was 6. Resting, postural, and action tremors lessened with treatment with levodopa (150 mg, 5 times a day), whereas
dystonia was unchanged. During a levodopa test, he had
a 70% improvement of the resting (baseline score = 1 and
treated score = 0) and postural (baseline score = 3 and

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A

B

C

D

E

F

Figure 2. Magnetic resonance imaging (MRI) of a coronal T1-weighted scan of patient 1 showing a left paramedian thalamomesencephalic infarct (A); an axial
T1-weighted scan of patient 4 showing a left medial mesencephalic infarct (B); an axial T1-weighted scan of patient 5 showing a large left mesencephalic infarct
associated with a left temporo-occipital infarct (C); an axial T1-weighted scan of patient 7 showing infarct in the right superior cerebellum, the right superior
cerebellar peduncle, and the upper part of the pons (D); and E, an axial T2-weighted scan of patient 3 (4 days after a stroke), showing a right paramedian
mesencephalic infarct involving the dopaminergic area. F, A control scan of patient 3, taken 1.5 years after (E), is axial, T1-weighted, and shows a small residual
tegmental lesion close to the aqueduct of Sylvius, sparing the nigrostriatal dopaminergic system. At the time of the study, dystonia was no longer present. Note a
decreased width of the right cerebral peduncle. The white line represents the anterior-posterior commissure.

treated score = 1) components of tremor. In the arm, rigidity (baseline score = 1 and treated score = 0) and akinesia (baseline score = 6 and treated score = 2) were also
lessened. Mild cerebellar hypotonia was present. Mild hypesthesia was observed in the hand and forearm.
CLINICAL FINDINGS
All patients had dystonia affecting the upper extremity
or face. With the exception of patients 1 and 6, all patients had mild or moderate dystonia. Patients 3 and 4
had mild dystonia of the hand within 2 to 3 days of the
initial stroke. Dystonia lessened in patient 4 and disappeared in patient 3 within 18 months. Patients 2 and 7
had mild dystonia of the fingers, which was noticed only
on neurologic examination and disappeared within 3
months. Patient 1 had severe dystonia of the arm and face
that developed while recovering from hemiparesis.
Parkinsonism consisting of “plastic” hypertonia associated with bradykinesia in alternative rapid movements was observed in patients 1, 2, 5, and 6. Patients 5
and 6 had 4-Hz distal resting tremor associated with irregular 5.5-Hz postural tremor in the upper extremity.
The delay in the onset of tremor after the midbrain lesion varied from 11⁄2 months to 1 year. Dystonia was not
the initial symptom in either of these patients and was
less disabling than tremor.
The effect of levodopa therapy was evaluated in 3
patients. Patients 3, 4, and 7 considered themselves to
be normal and were not treated. Patient 2 refused the treatment. Patients 5 and 6 showed a 70% resolution of rest-

ing and postural tremor and of rigidity and akinesia in
the arm. In patient 1, a 30% lessening of rigidity of the
arm was observed. The reversibility of the effect of treatment was assessed: scores returned to the baseline values after the withdrawal of levodopa. In patients 1, 5, and
6, dystonic postures were unchanged after the longterm administration of levodopa, even when the doses
were increased to 750 mg/d.
Cerebellar hypotonia and dysmetria were observed
in all patients but patient 1. Coarse cerebellar action
tremor of proximal distribution in the upper extremity
was observed in patient 7. A neurologic examination
showed mild sensory impairment in patients 1, 5, and 7.
MRI FINDINGS
Figure 1 shows the extent of the lesions, and Table 2
summarizes the neuroanatomical findings. Lesions affecting the upper midbrain in patients 1 through 6 were
contralateral to the dystonic movements. In patient 7, the
lesion was ipsilateral to dystonia, being situated in the
lower midbrain and pons. The superior cerebellar peduncle was damaged before the decussation, and the ipsilateral superior cerebellum was also involved. In patients 1 through 6, the lesion involved the superior
cerebellar peduncle after the decussation (patients 1 and
4-6). In patient 1, the lesion was more ventral, involving only a small part of the superior cerebellar peduncle. In patient 3, these cerebellar fibers were involved at the time of the first MRI examination (Figure
2, E), but the lesion was no longer visible in that area on

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Table 2. Localization of Lesions*
Patient No.

1

2

3

4

5

6

7

Side of lesion/dystonia
Red nucleus
Superior cerebellar peduncle
Rubro-thalamic fibers
Decussation
Dentato-rubral fibers
III nucleus
Medial lemniscus
Central tegmental tract
Dopaminergic structures
Substantia nigra
Perirubral and retrorubral area
Ventral tegmental area
Nigrostriatal fibers
Thalamus
Medial
Parafascicular
Voi
Intralaminar
Medial subthalamic area
Forel field
Associated lesions

L/R
+

R/L
+

R/L
(+)

L/R
+

L/R
+

R/L
+

R/R

+
+

+
±

(*)
(*)

+
+

+
+

+
+

+

+

+

+
+
+

+
+

+
+

+
+

+

+

+

+

R MCA,
L PCA

L medial
parietal scar

±

+
+

+
+

+
+
+
+
+
±

+
+

(*)
(*)

+
+

+

+
Mild LA

R superior cerebellar
hemisphere

*L indicates left; R, right; +, involvement of the structure; (+), very mild involvement of the structure; ±, questionable involvement of the structure; (*), the
structure was involved on the first magnetic resonance imaging scans (4 d after the stroke) but not on follow-up magnetic resonance imaging scans (at 6 mo);
Voi, ventral oral internal nucleus; LA, leucoaraiosis; MCA, medial cerebral artery; PCA, posterior cerebral artery; and empty cells, the clinical sign is absent.

Table 3. Fluorodopa (F 18) Uptake: Individual Ki Values*

Patient
No.

Side of
Lesion/
Dystonia

Right

Left

Right

Left

1
2
3
4
5
6
7

L/R
R/L
R/L
L/R
L/R
R/L
R/R

0.007
0.012
0.009
0.010
0.008
0.004
0.010

0.003
0.005
0.010
0.008
0.005
0.010
0.012

0.010
0.006
0.008
0.010
0.008
0.004
0.008

0.002
0.005
0.009
0.005
0.001
0.008
0.009

Caudate Nucleus

Putamen

*Ki values are expressed as per minute. The mean ± SD right and left
pooled values in the caudate nucleus and the putamen of 11 control subjects
is 0.010 ± 0.002 and 0.010 ± 0.002, respectively, and those of 13 patients
with Parkinson disease is 0.005 ± 0.002 and 0.003 ± 0.001, respectively.
L indicates left; R, right.

follow-up scans (Figure 2, F). The red nucleus (mainly
the caudal and ventromedial parts) was involved in patients 1 through 6. The medial and parafascicular nuclei
of the thalamus (paramedian territory) were involved in
patients 1, 2, 5, and 6. In patient 1, the lesion also extended to the most medial part of the ventral oral internal nucleus and intralaminar nuclei. In patient 5, the paramedian thalamic infarction was bilateral.
The dopaminergic nigrostriatal system was damaged in patients 1 through 6. In patient 2 (who had mild
dystonia at examination), the lesion was situated more
superiorly than in the other patients. In patient 3 (who
recovered from dystonia), the lesion involved these fibers at the time of the first MRI examination (7 days after the onset). Follow-up MRI scans (18 months later),

however, showed shrinkage of the lesion, which was no
longer visible in the area of the nigrostriatal pathway. No
involvement of this pathway was observed in patient 7.
Dopaminergic cell bodies were affected in patients 1, 2,
4, 5, and 6. In patients 1, 2, and 4, the lesion damaged
mainly the ventral tegmental area. The perirubral and retrorubral areas and the pars compacta of the substantia
nigra showed lesions in only patients 5 and 6 with resting tremor. These 2 patients and patient 7 also had involvement of the central tegmental tract and the medial
lemniscus. Last, in patient 1, the lesion was close to the
pallidothalamic fibers in the Forel field. Additional lesions were also observed, including right lateral occipitotemporal and supramarginal gyri infarctions (patient
5), left parietal traumatic scar (patient 6), and mild leukoaraiosis (patients 2 and 7).
PET FINDINGS
The [18F]fluorodopa Ki values obtained in the 7 patients
are shown in Table 3, in which the radioactive Ki values obtained in control subjects and patients with severe Parkinson disease are also indicated. Four patients
with dystonia (patients 1 and 4-6) had lower Ki values
than did controls in the putamen ipsilateral to the mesencephalic lesion and contralateral to the dystonia. In the
caudate nucleus ipsilateral to the lesion, the caudate Ki
values were also decreased in 3 of these subjects, patient
4 having a caudate Ki in the normal range. In addition,
the decrease of Ki values in patient 2 was bilateral in the
putamen and contralateral to the lesion in the caudate
nucleus, but in this patient, the lesion crossed the midline. In these 5 patients, the mean ± SD radioactive Ki val-

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COMMENT

Dystonia resulting from a midbrain stroke was found in 7
of 48 patients with unilateral poststroke focal dystonia. In
3 of the 7 patients, tremor was observed: 1 patient had isolated cerebellar tremor, and the other 2 patients had resting and postural tremor that responded to levodopa treatment. Mild cerebellar signs (n = 6) and parkinsonism (n = 4)
were also observed. The lesions involved the cerebellar
pathways in all patients, the red nucleus area in 6, and the
nigrostriatal dopaminergic system in 5.
CLINICAL CHARACTERISTICS OF DYSTONIA
AND TREMOR IN PATIENTS WITH
MESENCEPHALIC LESIONS
Dystonia affected the distal part of the upper extremity
without involvement of the lower extremities. A constant feature was the abnormal posture of the hand, with
a permanent hyperextension of 1 or more fingers. The
severity of dystonia depended on its intensity at the start
of the disease: mild dystonia disappeared within a few
weeks (patients 2, 3, and 7); when the dystonia was more
severe, the evolution varied from mild improvement (patient 4) to an extension of dystonia to include the face
(patient 1). These characteristics are difficult to compare
with those of previously reported cases. In a revised study
of the Benedikt syndrome,4 Souques et al19 described the
dystonic postures of the arm and hand with flexed elbow
and flexed fingers. Dystonia of mesencephalic origin has
rarely been noticed in either computed tomographic or MRI
scans5-7,20,21 or mentioned in pathological studies.19,22 Dystonia associated with isolated infarct of the pons23,24 or central pontine myelinolysis25 is rare.
In our study, the sign most frequently associated with
dystonia was cerebellar dysmetria, observed in all patients except patient 1. Mild sensory impairment was
observed in patients 1, 5, and 7. Parkinsonism—consisting of akinesia and plastic rigidity ipsilateral to dystonia—was present in patients 1, 5, and 6. In patient 2,
whose dystonia was transient and noticed only on the
initial neurologic examination, parkinsonism was mild.
Such parkinsonian features, ipsilateral to dystonia6,7 and
located contralaterally to the predominant mesencephalic lesions, have already been reported. In some pa-

16
14
12

Dystonia Score

ues for the ipsilateral caudate nucleus lesion (0.006 ± 0.003
Ki/min) and putamen (0.004 ± 0.002 Ki/min) were in the
range of the Ki values observed in patients with severe
parkinsonism (Table 3). Conversely, in patients 3 and
7, the striatal Ki values were in the normal range. Dystonic signs tended to be more severe in patients with striatal dopaminergic denervation (dystonia score = 6.8 ± 4.1,
n = 5) than in patients with normal Ki values (dystonia
score = 1 for patients 3 and 7). This is further suggested
by the negative correlation between whole striatal Ki values ipsilateral to the midbrain lesion and the score of dystonia in the 7 patients (df = 5, r = −0.93; P,.005)
(Figure 3). For the last analysis, the mean striatal Ki was
used in view of the correlation between caudate nucleus
and putamen Ki values.

10
8
6
4
2

0

0.002

0.004

0.006

0.008

0.01

Mean Ipsilesional Striatal Uptake, K i/min

Figure 3. Correlations between whole-striatum absolute uptake values ( Ki
per minute) ipsilateral to the midbrain lesion and the dystonia score in the
7 patients. The higher the score, the more severe the dystonia. The dystonia
score is the sum of the scores for each part of the body of the provoking
factor (0 indicates no dystonia; 4, dystonia present at rest) 3 the severity
factor (0 indicates no dystonia; 4, dystonia present most of the time).
Maximal possible score is 120.

tients, however, bilateral parkinsonian manifestations were
observed, although dystonia remained unilateral.10,26
When observed in our group, tremor was of the resting and postural type (patients 5 and 6) and associated
with both ipsilateral minimal plastic rigidity and akinesia and cerebellar dysmetria (patient 7). Resting and postural tremor was markedly lessened by levodopa therapy,
in contrast to dystonia, where no abatement occurred.
Such complex tremor has already been reported following mesencephalic infarction,7,24,27 hemorrhage,10,28 or head
injury,29-32 consisting of a combination of resting and postural components, with a proximal and distal distribution6,7,10,33 and a slow frequency of 3 to 4 Hz.34
Mesencephalic lesions, as seen in our patients, resulted in the varied association of dystonia, cerebellar
manifestations, akinesia, plastic rigidity, and resting and
postural tremor.
NEURONAL BASIS OF DYSTONIA AND TREMOR
IN PATIENTS WITH MESENCEPHALIC LESIONS
Dystonia
In agreement with previous reports,5-7,19,22,26,32,33,35 the structures most frequently damaged were the ventromedial
mesencephalon, including the ventral tegmental area and
the medial part of the substantia nigra, the nigrostriatal
pathway, the superior cerebellar peduncle, and the red
nucleus area.
The present data suggest that dopaminergic denervation plays a major role in the occurrence of symptomatic dystonia due to a midbrain stroke. First, the 5 patients with the most severe dystonia were those with a
marked decrease in [18F]fluorodopa uptake in the ipsilateral striatum (Table 3 and Figure 1). The Ki values were
within the range of those found in patients with severe
parkinsonism.16 Second, there was a correlation between striatal Ki values ipsilateral to the lesion and the
dystonia score (Figure 3). Third, the 2 remaining patients, who had normal striatal Ki values, had only mild

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A

B

C

1
2

1

2

4
4

1

3

2

4

1
3

2
3
4

D

E

LV

M

LV

F

Fx
Zo

A
Do

Hb

IC

L

SPv

AC

FI
ML
T
CT

III F

III F

SCP

STN

RN

MB

OT

SCP

5

MLF

ML

G

CTT 6
5

SN

NSF

7
P

CP

RN

SN

5

SN

GP

HT

SCP
DCSP
6

Rt

Vop

Lam
RN

Ci

MB

Voi

M

II

Cs

am
Vim

5

6
5

U

6
6

7

7
6

Figure 4. Schematic representation of the ischemic lesions of the mesencephalon. All lesions are represented on the left side for easier comparison and
superimposed on the atlas of Hassler. In sagittal views (A and D), the thick semicircles traversed by a horizontal line indicate the anterior commissure (AC) on the
right and the posterior commissure (PC) on the left. In coronal views (B and E), the horizontal lines indicate the AC-PC plane. In axial views (C and F), the vertical
bars indicate the AC (upper)–PC (lower) line, and the horizontal lines, the middle of the AC-PC line. The lesions of patients 1 through 4 (circled numbers), who
have isolated dystonia, are outlined on A through C and those of patients 5 through 7, who have associated tremor, are outlined on D through F. A indicates
anterior nucleus; Ci, inferior colliculus; CP, cerebral peduncle; Cs, superior colliculus; CTT, central tegmental tract; Do, dorsal oral nucleus; DSCP, decussation
of the superior cerebellar peduncle; Fx, fornix; G, lateral geniculate body; GP, globus pallidus; Hb, habenula; HT, hypothalamus; IC, internal capsule; Lam,
intralaminar nuclei; LV, lateral ventricle; M, medial nucleus; MB, mamillary body; ML, medial lemniscus; MLF, medial longitudinal fasciculus; NSF, nigrostriatal
fibers; OT, optic tract; P, pons; Rt, reticular nucleus; RN, red nucleus; SCP, superior cerebellar peduncle; SN, substantia nigra; SPv, substantia periventricularis;
STN, subthalamic nucleus; III, third nucleus; III F, third nerve fibers; U, uncus; Vim, ventral intermediate nucleus; Voi, ventral oral internal nucleus; Vop, ventral
oral posterior nucleus; and Zo, zona incerta.

and regressive dystonia. Moreover, in patient 3, the evolution of dystonia paralleled the regression of the size of
the lesion in the ventromedial mesencephalon (Figure
2, E). These data suggest that dystonia is severe and persistent when dopaminergic nuclei and the nigrostriatal
pathway are involved. The lack of abatement of dystonia by prolonged high-dose levodopa treatment may be
explained by the fact that a lesion of nondopaminergic
structures—such as the cerebellothalamic fibers, the serotonergic system,36 and the cholinergic efferent projections of the pedunculopontine nucleus37,38—also plays
a role in midbrain dystonia or that sensorimotor reorganization beyond the nigrostriatal pathways is delayed.39
Lesions of other structures were less consistent.
Damage to the thalamus was observed in 4 patients and
affected the paramedian territory (patients 1 and 2), as
already described.1-3,5,39-41 Paramedian thalamic infarcts,
however, are frequently associated with subthalamomesencephalic lesions.5 Thus, it remains unclear in these
patients whether dystonia results from damage to the
paramedian territory of the thalamus or to the subthala-

momesencephalic area. The contribution of rubral and
perirubral lesions to dystonia is difficult to assess. Although these structures are almost consistently damaged, as shown in previous reports6,7,19 and in this study,
lesions of this area never occurred in isolation in our
patients.
When dystonia was severe and did not improve with
time, the lesions mainly involved the nigrostriatal pathway and the structures in the close vicinity. This suggests that direct dopaminergic dysfunction is mandatory for the persistence of dystonia.
Tremor
Tremor in patient 7 was characteristic of action cerebellar tremor and was associated with hypotonia. This was
consistent with the presence of a lesion of the cerebellum
and cerebellothalamic fibers in the pons. The movement
disorder was thus ipsilateral to the lesion. Patients 5 and
6 had resting and postural tremor, which lessened with
levodopa therapy. This suggests that lesions of the nigro-

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striatal dopaminergic system play a role in the occurrence of such midbrain tremor, as already shown clinically7 and experimentally.8,9 In contrast to patients with
isolated dystonia (patients 1-4), patients 5 and 6 had lesions located more laterally and dorsally in the substantia
nigra that also affected the perirubral and retrorubral areas (Figure 3 and Figure 4). This is in agreement with
the observation that dopaminergic cell loss in the perirubral and retrorubral areas in Parkinson disease preferentially occurs with severe tremor.42 It suggests that involvement of this area is essential for the occurrence of the resting
and postural component of the tremor. Involvement of the
“rubro-olivocerebellorubral loop” and of the medial lemniscus (observed only in patients 5 and 6) may also be necessary for the occurrence of tremor, however. Experimental data in monkeys have shown that only combined lesions
of the dopaminergic pathway and the rubro-olivocerebellorubral loop result in sustained tremor.9
CONCLUSIONS

Patients with dystonia alone and dystonia with tremor
had lesions in different parts of the mesencephalon.
Tremor occurs when lesions involve both the perirubral
and retrorubral dopaminergic system and the rubroolivocerebellorubral loop.
Accepted for publication October 28, 1998.
Corresponding author: Marie Vidailhet, MD, Department of Neurology, Hôpital Saint Antoine, 184 rue du faubourg Saint Antoine, 75012 Paris, France (e-mail:
marie.vidailhet@sat.ap-hop-paris.fr).
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