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Dopa-responsive dystonia [18F]dopa positron emission tomography.

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Dopa-responsive Dystonia:
El*F}Dopa Positron Emission Tomography
G. V. Sawle,'f K. L. Leenders,'? D. J. Brooks,"$ G. Hamood,§ A. J. Lees,$
R. S. J. Frackowiak,"f and C. D. Marsdenf
The syndrome of dopa-responsive dystonia comprises a minority of patients with dystohia, yet it is of considerable
diagnostic importance because patients respond dramatically to L-dopa therapy. Benefits from this treatment are
lasting, and the problems associated with long-term L-dopa therapy in patients with Parkinson's disease are generally
absent. It has been suggested that this condition is due to a defect in the dopamine synthetic pathway, which is
bypassed when patients are treated with L-dopa. We have studied [''Fjdopa uptake in 6 patients with classic doparesponsive dystonia (5 familial patients and 1 sporadic patient), aged 18 to 66 years. Data have been analyzed according
to a graphic approach, calculating an influx constant for each region studied. We have also studied a seventh, clinically
atypical, patient with juvenile dystonia-parkinsonism. Similar data have been calculated for a group of 10 healthy
control subjects and 10 patients with Parkinson's disease. The 6 patients with typical dopa-responsive dystonia had a
modest but significant reduction in the uptake of tracer into both caudate and putamen, which indicates a defect in
the decarboxylation, vesicular uptake, and storage of [ '*F)dopa This argues against the proposition that doparesponsive dystonia is due to an inherited defect of tyrosine hydroxylase alone. In the atypical patient, however, we
found a greater reduction of {'8F]dopa uptake into both caudate and putamen, comparable with that in patients with
Parkinson's disease.
Sawle GV, Lecnders KL, Brooks DJ, Harwood G, Lees AJ, Frackowiak RSJ, Marsden CD. Dopa-responsive
dystonia: ["Fldopa positron emission tomography. Ann Neurol 1991;30:24-30
Corner [l}was probably the first to recognize familial
childhood-onset dystonia with diurnal variations in severity, although it was the description by Segawa and
colleagues 121 of two cousins with an apparently hereditary dystonic syndrome, diurnal fluctuation, and a remarkable response to L-dopa that drew attention to this
disorder. Since then, many similar patients have been
reported. Different authors have described the same
condition as "progressive dystonia with marked diurnal
variation" {3], "fluctuating dystonia responsive to levodopa" [4},"diurnally fluctuating hereditary progressive
dystonia" [51, "hereditary dystonia-parkinsonism of juvenile onset" [GI, and "dopa-responsive dystonia" "7).
The patients in these reports generally have had a disease onset before the age of 10 years, with dystonia
affecting the legs o r gait and no other etiological explanation. The symptoms have been dramatically responsive to L-dopa. Many patients have been familial, usually suggesting autosomal dominant inheritance with
variable penetrance [S). Many patients, but not all,
have noticed a pronounced diurnal variation in symptoms with less severe symptoms in the morning or after
daytime sleep.
Because the response to L-dopa treatment is usually
excellent and remains so for many years, it has been
suggested that the cause of this condition may be a
defect in the dopamine synthetic pathway. Positron
emission tomography (PET) scans using tracer quantities of 6-L-['sF)fluoro-dopa (I"Fldopa) demonstrate
the integrity of part of this pathway. We have used
this technique to study a spectrum of patients with
juvenile-onset dopa-responsive dystonia to investigate
the anatomical and biochemical defect responsible for
this disease.
From "MRC Cyclotron Unit, Clinical Sciences Section, Hammersmith Hospital, ?Paul Scherrrr Institute, Villigen, Switzerland, SDepartment of Clinical Neurology, Institute of Neurology, National
Hospitals for Nervous Diseases, and §Department of N e u m l o ~ ,
Brook General Hospital, Shooters Hill, London, England.
Received Jd 5 , 1990. and in revised form Oct 30 and Dec 26.
Accepted o r publication Dec 3 1, 1990.
Methods
Six patients with classic dopa-responsive dystonia (DRD)
have been studied (Table 1).Five patients (Patients 2-6) came
from four families; the sixth (Patient 1) was a sporadic but
otherwise typical patient. We also include the results from a
seventh atypical sporadic patient who has been described in
at least two ocher reports as having dopa-responsivedystonia
T9, 101.
Putient Histories
PATIENT 1. At the age of 11 years, this woman's right foot
began to adopt an equinus posture when walking. During the
Address correspondence to Dr Sawle, MRC Cyclotron Unit, Clinical
Sciences Section, Hammersmith Hospital, DuCane Road, London
W12 OHS, England.
24 Copyright 0 1991 by the American Neurological Association
next 3 years, this problem worsened; although she was quite
normal immediately in the morning, by evening her foot
became inverted and tremulous, even at rest. After 4 years,
she noted some tremor in her right hand, although there was
no evidence of bradykinesia or rigidity. At this time, she
began receiving L-dopa. Within 1 week she noted pronounced improvement, and within 1 month she had returned
to normal, taking 50 mg of L-dopa (with benserazide) three
times daily. She has had no side effects from treatment.
There was no family history of similar illness.
2. At 8 years of age, this man started to “throw”
his left leg when walking, particularly toward the end of the
day. Within 1 year, he began to develop similar symptoms
on the right side. H e walked on tiptoes. After another year,
treatment with benthexol hydrochloride was started. Five
years later, he developed parkinsonian facies. After 2 1 years
(now aged 36 years), he had symptoms present all day, although he was much worse toward the evening. L-Dopa was
started with an immediate reduction in leg tone and an improvement in balance. For the past 12 years, the patient has
worked as a truck driver. His only complaint is of stiffness
in the legs after strenuous exercise. H e remains free of treatment complications, taking 100 mg of L-dopa (with carbidopa) four times daily. His sister, father, and son are similarly
affected.
PATIENT
3. This woman first noted symptoms at the age of
6 years. She started walking on her toes, tripping and falling.
PATIENT
She was unsteady when running. By her teens she could
only walk a few steps with assistance, and she subsequently
became wheelchair bound. She had pronounced axial rigidity
and a resting tremor of the limbs. Her voice became hoarse
and quiet. Despite these severe symptoms, she was almost
asymptomatic on waking in the morning. At the age of 52
years, she received her first dose of L-dopa. The response
was dramatic. Within days she was able to walk, and gradually
she regained the use of her hands, although speech never
returned to normal. She now goes dancing and leads an entirely normal life. She has taken 250 mg of L-dopa (with
carbidopa) once daily for 14 years without any treatment
complications. Other family members are affected, including
her mother, a brother, a sister, 1 niece (Patient 4 ) , and probably her maternal grandfather.
PATIENT 4. This woman is the niece of Patient 3. She developed poor balance with inversion of both feet and stiffness
of the hands when at school at age 10 years. At the age of
12 years, she developed torticollis to the right. By this time,
she was sometimes unable to walk, although symptoms were
much less severe in the morning. By the age of 35 years she
had developed rigidity of the arms, and her gait was highly
abnormal with pronounced stiffness of both legs. She began
receiving L-dopa at the same time as Patient 3, when aged
44 years, and has remained well on 125 mg of L-dopa (with
carbidopa) taken once daily for 14 years.
PATIENT 5. This woman had a normal birth and delivery.
She crawled at 9 months and walked unaided at 18 months,
although she walked on her toes and was unable to run. After
an attack of measles at the age of 30 months, she stopped
walking and developed a predominantly right-sided tremor.
By the age of 6 years, she was still not walking. She was alert,
but dysarthric and dysphonic. She had dystonic posturing in
the arms with bilateral arm tremor and cogwheel rigidity.
Her legs were similarly affected with a pronounced increase
in adductor tone. She deteriorated such that she lay in bed
with her legs scissored and back arched. She was hardly able
to move her arms. At the age of 8 years, she was treated
with L-dopa and developed chorea, although when she was
subsequently stabilized on 125 mg three times daily (without
a peripheral decarboxylase inhibitor), she became almost normal. The dose was subsequently increased as she grew, although she has been taking 250 mg four times daily for the
last 9 years without any treatment complications. She has a
similarly affected brother, who had the onset of symptoms
at age 4 years with diurnal fluctuations.
PATIENT 6. This woman developed a tremor of her hands
at the age of 12 years. She subsequently developed difficulty
with handwriting and tended to spill and drop things. By the
age of 19 years, she had increased muscle tone in all four
limbs with cogwheeling in the arms on reinforcement. She
had involuntary rocking movements of the trunk, with
flexion of the legs and dystonic posturing of the feet on
walking. She did not notice any diurnal variation. After starting L-dopa treatment, her involuntary movements, rigidity,
and tremor resolved within weeks. She currently takes 200
mg of L-dopa (with carbidopa) three times daily. Her mother
has a similar condition, which began at the age of 16 years.
She, too, has been treated with L-dopa in the last year with
resolution of her symptoms.
PATIENT
7. This man, although reported in the literature
lo}, is atypical. Although he
presented with juvenile dystonia-parkinsonism and has responded to L-dopa therapy, he has required unusually large
doses of L-dopa. H e has developed clear wearing-off with a
short duration of therapeutic action on chronic treatment.
H e first developed an unsteady gait at the age of 7 years. At
the time, he stood and walked with his back flexed and the
knees bent, with a tendency for the feet to assume an equinus
position. There was a slight but variable hand tremor, and he
fell when turning rapidly. His gait worsened toward the end
of the day. At his worst, he had to crawl around the house.
At the age of 9 years, he was treated with L-dopa with a
dramatic effect. By the age of 12 years, he was walking with
stiff legs and tremulous arms, but after 100 mg of L-dopa
(with carbidopa) he would return to normality, attending
school and playing sports. At midday, he took a second dose
of L-dopa, but by 4 PM he sometimes noted difficulty in
walking. A third tablet would restore function to normal until
bedtime. Over the following 7 years, his drug dosage has
increased to 800 mg daily (with a peripheral decarboxylase
inhibitor), taken in eight 2-hourly doses. If he delays a dose
he becomes immobile, and if he takes a dose too soon he
develops involuntary jerky movements of the legs. Nevertheless, after treatment with L-dopa for 10 years, he remains
well-controlled and is captain of his local football team. On
examination, he has a minimal tremor of the arms and a
little akinesia, but no other signs. Although this patient was
adopted, it has been possible to contact his natural parents,
as a patient with DRD [9,
Sawle et al: PET Scanning in Dopa-responsive Dystonia
25
Tuble 1. Clinical Details of Patients with Dopa-responsive Dystoniu
Patient
Age when scanned
Sex
Age at onset
Family history
Legs affected more than arms
Diurnal variation
Parkinsonism'
1.-dopa responsive
Duration of L-dopa therapy
Daily L-dopa dose (mg)
1
2
3
4
5
6
I
18
F
11
47
M
66
F
6
58
F
10
25
F
3
19
F
19
M
8
++
+
+
+
++
++
2 Yr
150
12 yr
400
-
+
+
0
+
+
+
+++
++
14 yr
250
+
+
+
+
++
14 yr
125
+
+
+
.+ +
++
17 yr
1,000d
12
+
7
a
-
+
-
+b
++
++
++++
++
9 mo
600
10 yr
800
'Patient adopted at an early age; family history believed to be negative.
bDiurnalvariation in early clinical history only.
'Parkinsonism has been rated according to the most severe parkinsonism recorded in the patients' medical history.
dThis patient is taking L-dopa alone. The other six patients take 1.-dopa in combination with a peripheral decarboxylase inhibitor (carbidopaor
benserazide).
0 = no parkinsonism; + = minor symptoms, including a reduction in arm swing and mild limb rigidity; + + = definite slowing of movement,
impassive facies, and mild tremor but without significant disability; + + + = more severe signs, including marked tremor or axial rigidity
leading to Significant disability; + + + + = obvious and disabling parkinsonism with postural instability.
and careful inquiry has revealed no evidence of a similar
disorder among his relatives.
The clinical details of all 7 patients are summarized in
Table 1.
Practical Procedure
['*F]-Dopa scans were performed at the same time of day
in each subject, with injection of tracer at approximately
11:30 AM. Patients took no medication after the previous
12 midnight. PET scans were performed on the CTI 981;
12/8 scanner (CTI, Knoxville, TN) at the MRC Cyclotron
Unit at the Hammersmith Hospital (London, England). The
performance characteristics of this scanner have been described by Spinks er al C11). Ethical permission for these
studies and for studies on normal volunteers was obtained
from the ethical committee of the Royal Postgraduate Medical School, Hammersmith Hospital. Approval to administer
radiolabeled gases and ligands was obtained from the Administration of Radioactive Substances Advisory Committee of
the United Kingdom. Written consent was obtained from all
subjects after a full explanation of the procedure.
Subjects were positioned in the scanner with the orbitomeatal line parallel to the detector rings, with the head in
an individually molded polyurethane support. A 10-minute
transmission scan was collected using a retractable 68Ga/68Ge
ring source. To block peripheral metabolism of tracer by
L-aromatic amino acid decarboxylase (AAAD), subjects received 100 mg of carbidopa 1 hour before the study and a
further 50 mg immediately before scanning. Each subject
received approximately 140 MBq (140 f 40 MBq) of
['*F)dopa by intravenous infusion over 2 minutes. Twentyeight frames of dynamic emission data were collected over
the following 124 minutes.
Scans were analyzed using image analysis software (Analyze version 2.0, BRU, Mayo Foundation, Rochester, MN)
26 Annals of Ncurology Vol 30 No 1 July 1991
on SUN 3160 computer workstations (Sun Microsystems,
CA). The position of striatal structures was determined by
inspection, with reference to the stereotactic atlas of Talairach and Tournoux [ 12). Regions of interest were defined for
caudate (1 region each side, 4 x 4 pixels; 1 pixel, 2.05 x
2.05 mm), putamen (3 contiguous regions each side, 4 x 4
pixels each), medial frontal cortex (1 circular region, 8-pixel
diameter), occipital lobe (1 circular region each side, 16pixel diameter), and cerebellum (dimensions as for occipital
regtons). The cerebellar and occipital regions of interest included both gray and white matter. All regions of interest
were defined on two adjacent planes using regions of identical sizes. Average values for each anatomical structure were
calculated. Regional time activity curves were plotted and
the data analyzed by using a multiple-time graphic analysis
approach 113-151 to calculate an influx constant (Ki) representing uptake of {'*F)dopa for each region of interest. The
activity in the occipital lobe was used as an indirect tissue
input for these calculations. Clinical asymmetries were minor
in each patient, and for this reason, both caudate and putamen K, values were calculated as an average of left and right
sides.
A group of 10 approximately age-matched normal subjects
was studied for comparison (mean age, 43 2 13 years). All
were normal on neurological examination. A group of 10
patients with Hoehn and Yahr [l6] grade 1-111 Parkinson's
disease (PD) has also been studied under the same protocol.
The parkinsonian patients, however, were older (mean age,
49 f 10 years). The mean duration of symptoms for the
parkinsonian patients was 5.8 f 3.2 years. Six of the parkinsonian patients were on no medication and, at the time of
scanning, had never received L-dopa. The remaining 4 parkinsonian patients were taking a mean of 650 mg of L-dopa
(with carbidopa/benserazide) daily, but this medication was
omitted after 12 midnight, the day before scanning. All nor-
Fig I . Images of cumulative {"FF,dopa uptake at the level of the
striutzm fram a patient with classical dopa-responsive djv-
tonia (DRD) (Case #4j, a patient with an atyptcal L-doparesponsive djistonic syndrome (Cuse #7j, and a healthy subject
and a patient with Hoehn & Yahr stage III idiopathic Purkinson's disease (PO). The patient with classical DRD shows
less accumulation of striatal tracer activity than the normal
subject, but more than the patient with PD. The atypicaE patient, in contrust, shows a dramatic reduction in tracer activity
of greater severity than in the PD patient.
mal control subjects and parkinsonian patients were scanned
at 11:30 AM the following morning. The K , values for the
patients with DRD were compared with K , values from patients with PD and healthy volunteers by using both unpaired
two-tailed t tests and Mann-Whitney U tests, with the Bonferroni correction for multiple comparisons c 17).
and mean P D value. Values for the medial frontal cortex (not shown) were similar in the three groups (mean
K, for normal subjects, 0.0024 k 0.0012; for patients
with DRD, 0.0028 ? 0.0005; for patients with PD,
0.0025 k 0.0014). Significance values for intergroup
comparisons for striatal structures are given in Table
2. The patients with classic DRD had caudate Ki values
that were significantly different from the normal subjects, but not significantly different from the patients
with PD. The patients with classic DRD had putamen
0.0180 7
0.0135
Results
Representative images of striatal { 18F)dopa uptake for
a healthy subject, a patient with PD, a patient with
classic D R D (Patient 4), and Patient 7 are shown in
Figure 1. The uptake of ['8F}dopa into caudate, putamen, and medial frontal cortex was calculated for each
subject. There were no significant left: right differences.
Figure 2 illustrates the mean striatal K, values for normal subjects and patients with PD (error bar, 2 x SD)
and the individual values for the patients with classic
DRD. Additionally, the atypical patient's (Patient 7)
values are given.
The 6 patients with classic D R D had caudate and
putamen Ki values that lay between the mean normal
T
N
9
n
3
Fi
0
0.0090-
D
2
20
L
L
aJ
0.0045-
u
(
r
0.0000
u*
1
Caudate
DRD
0
1
Putamen
Fig 2. Caudate and putamen injux constant (K,) values for
["F}dopu are shown for the normal and Parkinson's disease
subjects (meun 2 standard deviations; n = 10 for each).
The individual subject values are shown far the classical doparesponsive dystonia patients and the atypical patient. * = Patient 7.
*
Sawle et al: PET Scanning in Dopa-responsive Dystonia
27
Table 2 . Intergroup Comparison p Values
from Unpaired Two-tailed t Tests after Bonferroni's Cowection
for Multiple Comparisons (Correction of 4)
p Value from Unpaired
Two-tailed t Test
~
~~
Group Comparison
Caudate
Putamen
Norm vs DRD
DRD vs PD
<0.02
<0.01
NS
<o.oo 1
Nonparametric (Mann-Whirney U test) analysis gave similar pattern
of significance (normal vs dopa-responsive dysronia caudate, p <
0.02; putamen p < 0.05; DRD vs PD caudate, NS; putamen p <
0.005).
Norm = normal subjects (n = 10);DRD = classical dopa responsive dystonia (n = 6); PD = Parkinson's disease (n = 10); NS =
not significant.
Ki values that were significantly lower than the normal
subjects' values, but significantly &her than the values
of the patients with PD. There was no significant correlation between duration of clinical symptoms and caudate or putamen Ki values, nor between the degree of
parkinsonism (see Table 1) and the caudate Ki values.
The degree of parkinsonism, however, was negatively
correlated with the putamen Ki value (Y = 0.68, p <
0.05) when all 7 patients were considered together.
Excluding the atypical patient (Patient 7) abolished the
significance of this correlation (Y = 0.158, p = NS).
The K, values for caudate and putamen in the atypical patient (Patient 7 ) were conspicuously lower than
those in the patients with classic DRD and were in the
lower range of the patients with PD. His uptake into
the medial frontal cortex was normal (Ki = 0.0029).
Discussion
Endogenous dopamine is synthesized from L-tyrosine,
which is converted by the enzyme tyrosine hydroxylase
(TH) [lS) using biopterin and molecular oxygen as
cofactors into 3,4-dihydroxy-~-phenylalanine
(L-dopa)
[19]. This is further metabolized to dopamine by the
action of AAAD. Normally, the rate-limiting step of
this reaction is the hydroxylation of tyrosine, although
biopterin is present in subsaturating concentrations and
could play a regulatory role.
Because of the dramatic response to L-dopa therapy
and a single postmortem report 1201, it has been suggested that D R D might be due to defective TH activity, which would be bypassed by L-dopa. An alternative
etiological possibility is a deficiency of biopterin [21),
which has been reported in some patients with DRD.
The single pathological patient report, of a woman
aged 39 years [207, suggested that there were round
and poorly pigmented cells in the substantia nigra, although cell numbers were probably normal. Because
dopamine is the precursor for neuromelanin, the lack
of cell pigmentation was taken to indicate a failure of
28 Annals of Neurology Vol 30 No 1 July 1991
dopamine synthesis. Reexamination of material from
this patient, however, has indicated regionally selective
neuronal damage in the substantia nigra, which also
contained several Lewy bodies, suggesting that this patient had young-onset PD [22]. Furthermore, the patient had developed "severe ballistic dopa-induced dyskinesia" in life, which would be unusual in typical
patients with DRD.
Nevertheless, several studies of patients with DRD
have reported a reduction in cerebrospinal fluid levels
of homovanillic acid [3, 231, implying a reduction in
catecholamine turnover. If DRD were due to a defect
of TH with preserved nigral neurones, this might explain the dramatic response to L-dopa, although genetic
linkage studies have shown no association between
DRD and the TH gene 1241. Nevertheless, a defect of
nigral TH activity has been a reasonable hypothesis
to explain the occurrence of classic D RD (despite the
autosomal dominant inheritance). If this were correct,
striatal dopamine synthesis from L-dopa might be expected to be normal; this can be tested in vivo (at
least in part) by measuring regional cerebral uptake of
("F)dopa.
After injection of (18F}dopa, this tracer is distributed
throughout the brain as a function of cerebral blood
flow. Within 10 to 20 minutes, measured activity
within most regions begins to fall, whereas in tissues
containing dopaminergic nerve terminals the signal increases further. The mechanism of this accumulation is
the conversion of ["F]dopa into ["F]fluoro-dopamine
by the action of AAAD within dopaminergic neurons
and subsequent concentration of [18F)fluoro-dopamine
within terminal vesicles 125-271. By measuring the
rate of accumulation of ['*F)dopa in the brain, we are
able to determine the functional capacity of the presynaptic dopaminergic pathway, although because the size
of the endogenous L-dopa pool is unknown, it is not
possible to calculate the rate of endogenous dopamine
production. Nevertheless, measurements of ["F)dopa
uptake accord with known functional deficits in both
experimental lesions and human disease. Thus, for
example, monkeys given l-methyl-4-phenyl-l,2,3,6tetrahydropyridine (MPTP) to render them parkinsonian to varying degrees show decreased 1'8F)dopa uptake in striatum, proportional to the degree of nigral
damage sustained C28). In patients with Parkinson's
disease, the degree of reduction in 1l8F)dopa uptake
as measured by PET [29} corresponds more closely
to the expected degree of nigral cell loss 1307 than to
the degree of dopamine depletion. The uptake of
['*F]dopa is probably a combined functional measurement of dopaminergic nerve terminal density and the
amount of AAAD present. There is usually very little
L-dopa present in striatal tissue because the removal of
a carboxyl group by AAAD has a very high velocity
with respect to L-dopa. If D R D were due to an abnor-
mality of the synthetic pathway before AAAD, we
might therefore expect the uptake of exogenous Ldopa or {l8F}dopa to be normal. Alternatively, if the
defect involved AAAD itself or nerve terminal numbers, then the conversion of exogenous L-dopa to dopamine and the uptake of [18F}dopa would be abnormal.
The 6 patients with classic DRD have a mild but
significant reduction of tracer uptake into caudate and
putamen. This indicates abnormal decarboxylation,
storage, or concentration of tracer. Our patients have
all been studied after at least 6 months' treatment with
L-dopa, and we do not know the effect of this medication on the uptake of {"F)dopa. Clearly, this possibility
could be addressed by either {"F)dopa PET studies in
L-dopa-ndive patients, or by scans shortly before and
after beginning L-dopa therapy in patients with Parkinson's disease. To our knowledge, data from such studies have not been reported. It may be that chronic
L-dopa therapy downregulates AAAD within the dopaminergic system. An alternative explanation is that a
true presynaptic dopaminergic functional deficit exists,
which perhaps contributes to the clinical rigidity in
some of these patients. Correlations between the degree of clinical parkinsonism (rated before medication)
and the measured 1"F)dopa uptake reached statistical
significance for the putamen, but not the caudate, although because this correlation was only significant
when including the atypical patient (Patient 7), we cannot necessarily conclude that the dopaminergic defect
is quantitatively related to the degree of parkinsonism
in typical patients with DRD.
Very few patients with DRD have been studied with
PET. Lang and associates [3 13 studied an 11-year-old
patient with disease onset at age 4 years. The patient
had generalized dystonia with diurnal fluctuation of
symptoms and resolution of dystonia on L-dopa. Further clinical details were not given., but the authors
reported reduced putamen { "F)dopa uptake on the
left, described as "looking very much like that seen in
idiopathic Parkinson's disease." Martin and colleagues
[32] studied 3 patients with "dopa responsive dystoniaparkinsonism." Two of these patients (1 woman aged
34 years and 1 man aged 43 years) were 5 years old at
presentation. At the time of scanning, one had dystonia
affecting gait and both arms, and the other had torticollis and writer's cramp. Both were described as responsive to L-dopa, but it is not stated whether the patients
were taking medication at the time of their PET studies. In these patients, {"Fldopa studies were normal.
The third patient, a woman aged 36 years at onset, had
reduced mean striatal { "Fldopa uptake. This woman
is outside the diagnostic criteria for DRD, by age of
onset alone.
In contrast to the 6 patients with classic DRD, Patient 7 stands apart. Clinically, he was atypical and the
results of his {"FJdopa scan were quite different, indicating a defect of the decarboxylation, storage, or concentration of {18F}dopa.Indeed, his scan appearance is
similar to that seen in patients with advanced PD. His
dependence on higher doses of L-dopa and the emergence of wearing-off phenomenon, both of which are
unusual in patients with classic familial DRD 1331, are
in accord with this conclusion. By convention, Parkinson's disease (by which we mean a specific distribution
of neuropathology affecting the substantia nigra with
Lewy bodies in remaining neurones) is rare in individuals younger than 40 years, but does occur after age
20 years when it is termed young-onset P D {34]. We
suspect that Patient 7 has pathology similar to that of
Parkinson's disease. The patient with presumed DRD
with age of onset at 6 years, who died at 39 years of
age [20], had nigral degeneration with Lewy bodies in
the remaining nigral cells. Perhaps, therefore, Lewybody Parkinson's disease can begin even in childhood.
Another puzzling and possibly related condition
is young-onset dystonia-parkinsonism, beginning between the ages of 20 and 40 years. Such patients present with dystonia in excess of that seen in patients
with PD 1353. They then develop parkinsonism (which
may or may not respond to L-dopa, often with worsening of their dystonia). There is no pathological proof
that this condition is due to PD. Such patients differ
from patients with DRD in that their response to Ldopa is not dramatic, they do not exhibit obvious diurnal fluctuation, and they are (in our experience) sporadic rather than familial patients. Two such patients
have been studied using PET and ["F)dopa 1361. Both
had reduced tracer uptake in the striatum contralateral
to the most severe symptoms, at a level intermediate
between healthy subjects and patients with Parkinson's
disease. These results cannot be directly compared
with the present study because a different PET camera
was used and data were analyzed only as a simple striatum: surrounding brain ratio. On clinical and PET evidence, therefore, we consider young-onset dystoniaparkinsonism to be a separate clinical entity, differing
from both Parkinson's disease and DRD. We have
presented {''Fldopa studies in a series of 6 patients
with classic DRD. All had a significant but mild reduction in striatal tracer uptake. This indicates a defect in
the decarboxylation, vesicular uptake, and storage of
[18F]dopa, and contradicts the proposition that this
condition is due to an inherited defect of TH alone.
G. V. S. is supported by the Parkinson's Disease Society of Great
Britain.
We thank colleagues at the MRC Cyclotron Unit, Radiochemistry
and Physics sections (Hammersmith Hospital, London, England),
whose expertise made these studies possible. We also thank Ms
C. J. V. Taylor and Mr G. C. Lewington for their considerable help
with scanning.
Sawle et
al:
PET Scanning in Dopa-responsive Dystonia
29
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