ORIGINAL ARTICLE

Cardiac sympathetic denervation in Parkinson’s disease patientswith SWEDDs

Wooyoung Jang • Joong-Seok Kim •

Jin Whan Cho • Young Hwan Kim •

Ji Young Kim • Yun Young Choi • Hee-Tae Kim

Received: 22 August 2012 / Accepted: 7 November 2012 / Published online: 24 November 2012

� Springer-Verlag Italia 2012

Abstract Dopamine transporter scans of some patients

who have been clinically diagnosed with Parkinson’s dis-

ease (PD) fail to reveal abnormal dopaminergic functioning

and are referred to as scans without evidence of dopami-

nergic deficits (SWEDDs). In this study, we investigated

the differences between SWEDDs patients and PD patients

using 123I-metaiodobenzylguanidine (MIBG) scans. This

study enrolled 20 patients with SWEDDs, 30 patients with

early PD and 50 healthy controls. Cardiac 123I-MIBG scans

were performed on all subjects, and parameters including

the early and delayed heart-to-mediastinum ratios (H/M)

and the washout rate were compared among the three

groups. The mean delayed H/M ratio in the PD group

(mean ± standard deviation, 1.45 ± 0.23) was the lowest

of the three groups, and the scans in the group without

evidence of dopaminergic deficits exhibited a lower mean

delayed H/M ratio (2.15 ± 0.48) than the control group

(2.56 ± 0.55) (p \ 0.05). The intermediate status of car-

diac MIBG uptake in the SWEDDs patients in our study

may have been due to the heterogeneity of the SWEDDs

patients; some of these patients had Parkinsonism with

unknown characteristics, some may have had early PD with

false-negative dopamine transporter imaging, and some

have had primary dystonia that was misdiagnosed as PD.

These uncharacterised SWEDDs patients accounted for a

larger proportion of the heterogeneous SWEDDs than

observed in previous studies, but our results suggest that

cardiac 123I-MIBG scans may help to differentiate patients

with SWEDDs from patients with PD.

Keywords SWEDDs � 123I-MIBG scintigraphy � FP-CIT

PET � Parkinson’s disease

Introduction

The degeneration of both nigrostriatal neurons and the car-

diac sympathetic nerve are well-established features of

early-stage idiopathic Parkinson’s disease (PD) [1, 2].

Functional imaging of dopamine transporters can be used to

identify nigrostriatal degeneration with high sensitivity and

specificity [1, 3]. However, some recent large clinical trials

have identified patients with clinically diagnosed PD who

show normal dopaminergic function imaging [4, 5]. In the

ELLDOPA trial, these patients were rescanned after 4 years,

and their follow-up scans again revealed normal dopami-

nergic activity [4]. Such findings have been referred to as

scans without evidence of dopaminergic deficits (SWEDDs)

in the subsequent literature. Schneider et al. [6] suggested

that dystonic tremor may be a primary cause of SWEDDs,

which was supported by a recent electrophysiological study

Electronic supplementary material The online version of thisarticle (doi:10.1007/s10072-012-1244-1) contains supplementarymaterial, which is available to authorized users.

W. Jang � H.-T. Kim (&)

Department of Neurology, College of Medicine,

Hanyang University, 17 Haengdangdong, Seongdong-gu,

Seoul 133-792, Korea

e-mail: kimht@hanyang.ac.kr

J.-S. Kim

Department of Neurology, Catholic University College

of Medicine, Seoul, Korea

J. W. Cho

Department of Neurology, Samsung Medical Center,

Seoul, Korea

Y. H. Kim � J. Y. Kim � Y. Y. Choi

Department of Nuclear Medicine, Hanyang University

College of Medicine, Seoul, Korea

123

Neurol Sci (2013) 34:1375–1382

DOI 10.1007/s10072-012-1244-1

of SWEDDs patients that found similarities with the physi-

ological characteristics of dystonia [7]. Although these

recent studies support the view that a large proportion of

SWEDDs cases are the result of diagnostic error, misdiag-

nosis cannot explain the entire spectrum of SWEDDs

patients.123I-metaiodobenzylguanidine (MIBG) is a physiologi-

cal analogue of noradrenaline that is taken up by and stored

in sympathetic neurons in a manner similar to norepi-

nephrine uptake, and these properties enable investigations

of the functional activity of postganglionic sympathetic

neurons [2]. Reduced cardiac MIBG uptake has been

reported in both early-stage PD patients and PD patients

with normal routine autonomic function tests [2, 8, 9].

However, previous studies have not compared SWEDDs

and PD patients using MIBG scintigraphy.

We hypothesised that cardiac MIBG scintigraphy of

SWEDDs patients would yield normal values if the

SWEDDs patients exhibited a pathophysiology that was

significantly different from that of PD patients; if this were

the case, this method could therefore be used to differen-

tiate SWEDDs patients from early PD patients. In this

study, we classified the 95 enrolled subjects as SWEDDs,

PD or control patients, depending on their clinical assess-

ment and [18F] N-(3-fluoropropyl)-2b-carbon ethoxy-3b-

(4-iodophenyl) nortropane PET (FP-CIT PET) findings.

We then compared the clinical characteristics and myo-

cardial MIBG uptake among these three groups.

Patients and methods

Patients

Twenty patients with SWEDDs, 30 patients with Hohen

and Yahr (H&Y) stage 1 or 2 PD, and 50 healthy controls

were recruited for this study. The SWEDDs patients were

defined by the following criteria: adult ([40 years of age)

onset of Parkinsonian symptoms, including asymmetric

resting tremor or akinetic rigidity; previous diagnosis of

PD by a specialist; and subsequent normal dopamine

transporter imaging (FP-CIT PET) 3 years after PD diag-

nosis. The patients in the PD group fulfilled the known

clinical PD criteria and had abnormal FP-CIT PET find-

ings. The patients with possible secondary causes for their

Parkinsonism were excluded.

All individuals in the control group were in good health

and had no medical history or medication use that could have

affected either their 123I-MIBG uptake or their dopamine

transporter imaging. Patients with relevant cardiac prob-

lems, medical disorders, histories of neuropathy, or current

medication use that could have influenced the FP-CIT PET/

CT or cardiac MIBG scintigraphy were excluded. Informed

consent was obtained from all subjects, and the study was

approved by the local ethics committee. Basic patient

demographic and clinical data were obtained from each

patient. Disease severity was evaluated according to the

UPDRS score and the H&Y stage. All Parkinsonian symp-

toms, such as bradykinesia, tremor and rigidity, in the

SWEDDs and PD patients were noted. The definition of

bradykinesia followed the UK brain bank criteria, which call

for a ‘‘progressive reduction in speed and amplitude of

repetitive actions’’. If there was only a reduction in speed, we

regarded this as ‘‘slowness’’. The non-motor symptoms of

the PD and SWEDDs groups were also evaluated according

to the non-motor symptoms scale (NMSS). The respon-

siveness to levodopa was also assessed. Good responsive-

ness to levodopa was defined as an improvement [20% of

the UPDRS score with respect to baseline [10].

Data acquisition

FP-CIT PET/CT

FP-CIT PET/CT was conducted in all SWEDDs and PD

patients and in 26 controls. Cardiac MIBG scans were per-

formed in all three groups. The PET/CT scans were per-

formed 2 h after an intravenous injection of an average of

185 MBq (5 mCi) FP-CIT. All subjects underwent PET/CT

imaging in a Biograph TruePoint 16 scanner (Siemens

Medical Systems, Hoffman Estates, IL, USA). The emission

PET data were acquired for 10 min, and the CT data were

used for the attenuation correction. The dopamine trans-

porter binding state was evaluated through visual analysis

and semiquantitative analysis of the FP-CIT PET/CT. In the

SWEDDs patients, the follow-up PET/CT images were used

for the analysis. Examples of initial and follow-up PET/CT

images are provided in supplementary Fig. 1. Semiquanti-

tative analyses were performed using the specific to non-

specific binding ratio (SNBR) and the asymmetric index

(AI). The regions of interest were identified and drawn on

both caudate nuclei, both putamen, and the occipital cortex.

Standardised uptake values were taken from each area, and

three adjacent slices where the striatum was best observed

were used for the analysis. The SNBR was calculated using

the following formula: (average standardised uptake value of

striatum-average standardised uptake value of occipital

cortex)/average standardised uptake value of occipital cortex

[10]. The AI was calculated according to (better uptake-

worse uptake)/better uptake [11].

MIBG scintigraphy

The successive cardiac MIBG scans were performed 20 min

and 3 h after the intravenous injection of an average

of 111 MBq (3 mCi) 123I-MIBG using a dual-head gamma

1376 Neurol Sci (2013) 34:1375–1382

123

camera (ECAM, Siemens Medical Systems, Chicago, IL,

USA). The cardiac and mediastinal regions of interest were

drawn for the semi-quantification of the 123I-MIBG uptake,

and the heart-to-mediastinum (H/M) uptake ratios and

washout rates (WR) were calculated using the following

formulas: H/M ratio = mean count of the heart uptake at

20 min/mean count of the mediastinum uptake at 3 h;

WR = {[mean counts of the heart uptake at 20 min-(mean

counts of the heart uptake at 3 h 9 1.1735 for decay cor-

rection)] 9 100/mean counts of the heart uptake at 20 min}.

The lower cut-off value for normal MIBG uptake was defined

as the mean minus 2 standard deviations of the control group.

Statistical analysis

The data were analysed using SPSS 12.0. The Kruskal–

Wallis, ANCOVA, Mann–Whitney, and Chi-squared tests

were used to compare the FP-CIT uptake of the striatum, H/M

ratios, WRs and clinical features among the three groups.

Differences with p \ 0.05 were considered significant.

Results

Clinical features

A comparison of the baseline demographic and clinical

data between the PD and SWEDDs patient groups is shown

in Table 1. No significant differences were observed with

respect to age, sex, disease duration or disease severity

between the groups. Only 12 of the 20 SWEDDs patients

had bradykinesia, whereas all of the PD patients had bra-

dykinesia (p \ 0.05). Slowness was observed only in the

SWEDDs patient group (p \ 0.05). Disease progression

and responsiveness to levodopa treatment were reported in

4 and 10 of the SWEDDs patients, respectively. Postural

tremor was observed in only 4 of the 16 tremulous

SWEDDs patients. Table 2 presents the detailed clinical

features of the 20 SWEDDs patients. Dystonia was

observed in only 2 of the 20 SWEDDs patients, and there

was a significant difference in the total NMSS score

between the two groups (PD, 21.57 ± 6.20; SWEDDs,

14.45 ± 5.76; p \ 0.05). Supplementary Table 1 includes

a description of the detailed clinical features among three

PD patients, SWEDDs with dystonia, and SWEDDs with

low cardiac MIBG uptake, and supplementary Table 2

shows a comparison of each component of the non-motor

symptoms between the PD and SWEDDs patients.

FP-CIT PET/CT

A non-linear decline in striatal uptake during normal age-

ing has been observed in FP-CIT scans [12]. Therefore,

adjustment by age was performed in this study. Significant

differences were observed in the SNBRs for both the stri-

atum and in the AIs for the caudate and putamen among the

three groups (p \ 0.01 in all areas, p \ 0.01 in both stri-

atum). In the post-hoc analysis using Tukey’s test after

ANCOVA, there were significant differences in the SNBRs

for both the striatum and in the AIs (caudate and putamen)

between the healthy control and PD groups (p \ 0.01 in all

areas, p \ 0.01 in both striatum). However, the SNSBs for

the striatum and the AIs were similar between the

SWEDDs patients and the healthy control group, and these

results were identical to the visual analysis of the FP-CIT

PET/CT. Table 3 shows the mean SNBRs for the caudate

and putamen and the AI indices for the caudate and puta-

men in each group. The FP-CIT PET/CT parameters in two

patients who had MIBG values less than two standard

deviations lower than the MIBG values in the control group

were similar to those in the normal healthy control group.

Cardiac 123I-MIBG scintigraphy

Because continuous data from the cardiac MIBG scans

were not assumed to have a normal distribution pattern for

statistical tests, the Kruskal–Wallis and two-sided Mann–

Whitney U tests were used for the group comparisons.

There were statistical differences among the three groups

in terms of the early H/M ratio, delayed H/M ratio, and WR

(p \ 0.01). Post-hoc analysis using the two-sided Mann–

Whitney U test demonstrated that the mean early H/M

ratios were higher in the control (mean ± standard devia-

tion, 2.37 ± 0.46) and SWEDDs patient (2.20 ± 0.49)

groups than in the PD group (1.53 ± 0.23, p \ 0.01 and

p \ 0.01, respectively). No significant difference was

observed in the mean early H/M ratios between the control

and SWEDDs patient groups. The delayed H/M ratio in the

PD group (1.45 ± 0.23) was the lowest of the three groups,

followed by those of the SWEDDs patient (mean

2.15 ± 0.48) and control (2.56 ± 0.55) groups (p \ 0.05).

The comparison of the delayed H/M ratio between the

SWEDDs patient and control groups also revealed a sig-

nificant difference (p \ 0.01). The WR in the PD group

(27.29 ± 7.22) was the highest of the three groups, fol-

lowed by the SWEDDs patient (18.15 ± 5.80) and control

(13.33 ± 7.39) groups (p \ 0.01). The WR in the

SWEDDs patient group was also significantly higher than

that in the control group (p \ 0.05). Figure 1 shows a box

plot of the mean H/M ratios and WRs for the three groups.

Figure 2 displays the visual differences in cardiac 123I-

MIBG uptake between the groups.

The lower cut-off value for the delayed H/M ratio was

calculated as 1.46, and two patients in the SWEDDs group

had ratios below this defined cut-off value. These two

patients also exhibited olfactory functioning that was

Neurol Sci (2013) 34:1375–1382 1377

123

abnormally low for their age. Twenty-seven patients in the

PD group and no patients in the control group had ratios

below the cut-off value.

Next, we separated the SWEDDs patients into two

groups based on the presence of bradykinesia and com-

pared the early and delayed H/M ratios, WR, and

Table 1 Demographic characteristics of patients in the SWEDDs and PD groups

SWEDDs (n = 20) PD (n = 30) p value

Age 67.95 ± 7.72 69.53 ± 7.83 0.93

Gender (male/female) 8/12 10/20 0.89

Disease duration (years) 3.75 ± 1.21 3.62 ± 0.69 0.953

Parkinsonian symptoms

Tremor 14 (70) 25 (83.3) 0.342*

Bradykinesia 12 (60) 30 (100) 0.03*

Rigidity 16 (80) 26 (86.7) 0.439

Slowness 8 (40) 0 (0) 0.03*

Axial involvement 4 (20) 12 (40) 0.122*

Non-motor symptoms scale 14.45 ± 5.76 21.57 ± 6.20 0.02

Good response to L-dopa treatment 10 (50) 30 (100) 0.01*

Disease progression 4 (20) 30 (100) 0.01*

UPDRS (part III) 19.7 ± 3.56 23.6 ± 5.12 0.362

Modified H&Y 1.65 ± 0.54 1.67 ± 0.4 0.97

These values represent the means with the standard deviations in parentheses or the number of patients with percentages in parentheses

SWEDDs scans without evidence of dopaminergic deficits, PD Parkinson’s disease, UPDRS united Parkinson’s disease rating scale, H&Y Hoehn

and Yahr staging of Parkinson’s disease

* Chi-squared test

Table 2 Clinical findings in 20 patients with SWEDDs

No. Sex Age

(years)

Duration

(years)

Parkinsonian

signs

H&Y

stage

UPDRS

(Part III)

L-dopa

response

Early H/M

ratio

Delayed

H/M ratio

Washout

Rate

Total

NMSS

1 M 71 7.5 TR, TP, B, R 2 15 Positive 2.07 1.84 26.19 12

2 F 67 3.2 TR, S, R 1 16 Negative 1.72 1.41 21.06 10

3 F 74 3.5 TR, B, R, A 1 10 Negative 2.89 3.06 15.36 16

4 F 58 3.5 TR, TP, S 1 4 Positive 1.65 1.79 19.39 21

5 F 68 3 TR, S, A 1 5 Negative 2.03 2.13 10.63 10

6 M 73 3 TR, B, R 2 13 Positive 2.45 2.13 22.98 8

7 M 68 3 TR, B, R 2 15 Positive 2.04 2.25 14.36 8

8 F 85 4.5 TR, TP, S, R 2 12 Negative 3.79 3.38 23.00 4

9 F 62 3.4 TR, TP, S, D 1 8 Negative 1.83 1.84 3.33 18

10 F 73 3 TR, B, R 2 17 Positive 2.20 1.95 26.46 15

11 M 57 3.8 TR, B, R 2 13 Positive 2.28 2.50 17.56 19

12 F 77 3 TR, B, R, A 2.5 14 Positive 2.17 2.30 20.97 6

13 F 55 3.2 B, R 2 12 Positive 2.47 2.72 11.22 16

14 M 70 5.5 TR, B, R 2 15 Positive 2.07 1.84 26.19 22

15 F 75 3 TR, B, R 2 19 Positive 1.80 1.45 26.57 18

16 M 67 3.2 B, R, A 2.5 18 Negative 1.90 1.80 18.24 24

17 F 60 3.6 S, R 2 22 Positive 2.01 2.00 15.44 22

18 M 58 3 S, D 2 21 Negative 1.98 1.90 19.82 16

19 M 68 3 B, R 2 27 Negative 2.12 1.98 14.90 14

20 F 72 3.8 S, R 2 16 Negative 1.96 1.85 16.78 10

B bradykinesia, S slowness, NMSS non-motor symptoms scale, R rigidity, D dystonia, A axial involvement, TR resting tremor, TP postural tremor

1378 Neurol Sci (2013) 34:1375–1382

123

parameters from the FP-CIT PET analysis between these

two groups. Although the WR values in the group of

SWEDDs patients with bradykinesia were slightly

increased as compared with those in the slowness group

(p \ 0.12), there were no statistical differences in any of

the parameters between the two groups (Supplementary

Table 3).

Discussion

In the present study, we observed that the clinical features of

SWEDDs patients, including the paucity of dystonia, rela-

tively high incidence of levodopa responsiveness and bra-

dykinesia, were quite different from those found in previous

studies and that the patients who responded to levodopa had a

relatively stable disease course. These findings are clearly

inconsistent with the findings of other recent studies and

indicate that the presence of dystonia and slowed movement

may not be specific to SWEDDs patients. Parameters from

the cardiac MIBG scans of SWEDDs patients were distinct

from those of the PD and control groups.

In recent studies, most SWEDDs cases are thought to

result from misdiagnosis. Schneider et al. [6] evaluated ten

patients with dystonic tremor and suggested that the

tremors may have been the cause of the SWEDDs. Another

study that examined the long-term follow-up of SWEDDs

patients revealed a misdiagnosis of dystonic tremors

resembling Parkinsonism [13]. These studies have sug-

gested that some of the features that distinguish SWEDDs

from dystonic tremor include a lack of clinical respon-

siveness to levodopa, signs of dystonia, a relatively stable

disease course, and the absence of true bradykinesia based

on the UK PDSBB diagnostic criteria [6, 7, 13]. More

recently, normal olfactory function and gait characteristics

that differ from PD have also been described as features of

SWEDDs patients, and an electrophysiological study of

SWEDDs patients using paired magnetic stimulation

revealed that the abnormal cortical plasticity in SWEDDs

patients was similar to that observed in dystonia [7, 14, 15].

There is also the possibility of other aetiologies in

SWEDDs patients. Sixel-Doring et al. [16] reported five

inconclusive SWEDDs patients who exhibited positive

levodopa responses, and Hall et al. [17] reported three

SWEDDs patients demonstrating expansion of the fragile

X mental retardation 1 (FMR1) gene. Therefore, the clin-

ical characteristics and significance of SWEDDs patients

remain unclear.

Bajaj et al. [13, 18] recently reported that bradykinesia

could be observed in SWEDDs patients, and another report

described the presentation of bradykinesia in dystonic tre-

mor. Thus, the large proportion of bradykinesia in our

SWEDDs group also indicates the difficulty of differenti-

ating SWEDDs from PD according to the presence of

bradykinesia. The paucity of dystonia in the SWEDDs

group was another characteristic finding of our study,

which may have been a result of the careful examinations

performed to exclude dystonic tremor because many pre-

vious studies have suggested that the misdiagnosis of

Table 3 123I-FP-CIT PET/CT results

SWEDDs

(n = 20)

PD (n = 30) Control

(n = 26)

Age 67.95 ± 7.72 69.53 ± 7.83 61.88 ± 1.88

Left caudate 3.31 ± 0.58 2.21 ± 0.80* 3.47 ± 0.38

Left putamen 3.41 ± 0.75 1.31 ± 0.77* 3.69 ± 0.40

Right caudate 3.28 ± 0.73 2.19 ± 0.71* 3.52 ± 0.65

Right putamen 3.54 ± 0.76 1.26 ± 0.60* 3.77 ± 0.38

Asymmetric index,

caudate

0.04 ± 0.03 0.10 ± 0.07* 0.04 ± 0.03

Asymmetric index,

putamen

0.05 ± 0.05 0.24 ± 0.16* 0.05 ± 0.03

Data are mean ± SD

FP-CIT PET/CT, [18F] N-(3-fluoropropyl)-2b-carbon ethoxy-3b-(4-

iodophenyl) nortropane PET; SWEDDs, scans without evidence of

dopaminergic deficits; PD, Parkinson’s disease

* p \ 0.01, adjusted by age

Fig. 1 Box plots of the heart-to-mediastinum ratios (H/M) and washout rates (WRs) in the SWEDD, PD and control groups (the circles above

and below the bar indicate outlier values)

Neurol Sci (2013) 34:1375–1382 1379

123

dystonia constitutes a large number of SWEDDs patients.

Therefore, this finding suggests that inconclusive SWEDDs

other than dystonia accounted for a larger proportion of the

heterogeneous SWEDDs as compared with those in pre-

vious studies.

Furthermore, of the 16 SWEDDs patients demonstrating

tremor, only four were found to exhibit a postural com-

ponent. Considering that dystonic tremors usually lack the

resting component and present mainly in a position-

dependent manner, although primary dystonia can also

present with asymmetric resting tremor and there is the

possibility that we missed subtle dystonic tremors, it is

more reasonable that the tremors in our SWEDDs patients

consisted of a heterogeneous disease entity than solely

primary dystonia or dystonic tremor [19].

In SWEDDs patients showing non-tremulous Parkin-

sonism, Fasano et al. [20] recently reported five patients

with primary progressive freezing gait, which could be

regarded as symptoms of Parkinsonism showing a normal

FP-CIT SPECT. This finding also supports the heteroge-

neity of SWEDDs patients.

We also observed that the NMSS score showed signif-

icant differences between SWEDDs and PD patients. In

particular, the scores for items related to olfactory function,

restless leg, constipation, and orthostatic dizziness were

also distinctive in the PD patient group. There was also a

report published suggesting that olfactory function could

be a differential marker between SWEDDs and PD groups,

and our NMSS data support this concept [15]. The

observed difference in non-motor symptoms between the

two groups might also reflect a different pathophysiology

between SWEDDs and PD.

The H/M ratios and WRs in the cardiac MIBG scans of

the SWEDDs group differed from those of both the control

and PD groups. Even early-stage PD is characterised by

abnormal cardiac MIBG findings [1, 2, 8, 9], and the study

by Chung et al. [21] suggested that the WR is a more

sensitive parameter than the H/M ratio. Therefore, the

differences between the PD and SWEDDs groups in terms

of the H/M ratio and WR may be explained if SWEDDs are

considered to indicate a disease other than PD. However,

the H/M ratio and WR differences between the SWEDDs

patients and the controls were unexpected in our study. The

cardiac MIBG SPECT results that we obtained support the

view that the pathophysiology of SWEDDs differs from

that of PD.

Sixel-Doring et al. [16] reported five cases of incon-

clusive SWEDDs in patients with positive responses to

levodopa after their clinical reassessments, and two of

these five patients showed normal findings on their follow-

up scan. In our study, the FP-CIT PET was repeated after

3 years for all patients in the SWEDDs group, and we also

Fig. 2 Cardiac 123I-MIBG images (anterior view at 20 min and 4 h after the injection with 111 MBq) for a patient with PD (a), a patient with

SWEDDs (b) and a healthy control patient (c)

1380 Neurol Sci (2013) 34:1375–1382

123

observed ten levodopa-responsive SWEDDs patients with

normal follow-up FP-CIT PET scans. Even after excluding

the two patients with low H/M ratios (which were within

two standard deviations of the mean value of the control

group) and the two patients with dystonia, the mean

delayed H/M ratio and WR of the SWEDDs group

remained significantly different from those of the control

group (p \ 0.04). This finding reinforces the possible

existence of inconclusive SWEDDs patients who are not

identified due to misdiagnosis and who exhibit a positive

levodopa response, a relatively stable disease course, and

mildly impaired sympathetic denervation.

We assumed that the differing H/M ratios and WRs

among the three groups were due to the heterogeneous

features of our SWEDDs patients. The two patients with

low H/M ratios had positive levodopa responses, abnormal

olfactory function tests, and progressive disease severity.

Ishibashi et al. [22] reported that a cardiac 123I-MIBG scan

alone delivers low diagnostic sensitivity, especially in early

PD. However, a high specificity for 123I-MIBG scans has

also been reported when conducted in early PD patients

[1, 22, 23]. Thus, in addition to these previous findings, the

low H/M ratios in the MIBG scans of the two aforemen-

tioned SWEDDs patients support the view that false-

negative findings are possible with FP-CIT PET scans

demonstrating high striatal uptake and no asymmetry, and

follow-up beyond 3 years may have revealed abnormalities

in the FP-CIT PET scans of these two patients. Further-

more, the detailed clinical features, including the progres-

sive nature, levodopa responsiveness, and presence of

bradykinesia, of these patients were similar to the charac-

teristics of three PD patients. In addition, one SWEDDs

patient with dystonia had clinical features that were similar

to those of previously studied patients with dystonic tremor

resembling Parkinsonism [6, 7, 13]. However, even after

accounting for the possibility of misdiagnosis and false-

negative values in the 123I-MIBG scintigraphy and FP-CIT

PET, it remained clear that a large proportion of the

SWEDDs patients in the present study differed consider-

ably from those described in previous studies.

One limitation of this study was its lack of confirmative

diagnosis, which would have required either long-term

follow-up or autopsy data. Therefore, the meaning of the

abnormal MIBG scans in these SWEDDs patients was

unclear. We also failed to demonstrate statistical differ-

ences in the parameters from the cardiac MIBG scans and

FP-CIT/PET between the SWEDDs patients with brady-

kinesia and SWEDDs patients with slowness. This finding

may have been due to the small sample size, which rep-

resents another limitation of this study. Thus, a large-scale

investigation with longer follow-up periods is required to

pinpoint the exact nature of SWEDDs.

Another limitation was the lack of perfusion scintigra-

phy to exclude heart disease or scarification, which have

been used by other studies comparing dopamine transporter

imaging (DAT) and MIBG scans. Finally, because of the

relatively low specificity for diagnosing PD by MIBG

scintigraphy, the possibility of false-positive MIBG results

in the SWEDDs patients should also be considered [24].

In conclusion, although our study was not the first to

compare DAT imaging and MIBG scintigraphy in patients

with suspected PD [1, 21], our results support the notion

that SWEDDs patients constitute a heterogeneous group

that may present with either a PD-like disease with

unknown characteristics or early PD, thereby generating

the potential for false-negative dopamine transporter

imaging results and misdiagnoses. Moreover, these incon-

clusive SWEDDs patients accounted for a larger proportion

of the heterogeneous SWEDDs cases than has been indi-

cated by previous studies. However, this assertion remains

speculative, and the majority of previously proposed

alternative diagnoses for SWEDDs should be assessed by

MIBG scintigraphy. In addition, only long-term follow-up

or autopsy studies will provide further clarification.

Acknowledgments This work was supported by a grant from the

Korean Health Technology R&D Project, Ministry for Health Welfare

& Family Affairs, Republic of Korea (A101712).

Conflict of interest The authors have no conflict of interest to

disclose.

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