Neurology Asia 2018; 23(3) : 245 – 251

Cervical dystonia in Parkinson’s disease:
Retrospective study of later-stage clinical features
Hiroshi Kida MD, 1,2,3Shiroh Miura MD, 4,5Yoshihiro Yamanishi PhD, 2,6Tomoyuki
Takahashi PhD, 1Takashi Kamada MD, 1Akiko Yorita MD, 1,2,3Mitsuyoshi Ayabe MD,
3
Hideki Kida MD, 1Tomoaki Hoshino MD, 1,2Takayuki Taniwaki MD
1,2,3

Division of Respirology, Neurology, and Rheumatology, Department of Medicine, Kurume University
school of Medicine, Kurume; 2Division of Gene Therapy and Regenerative Medicine, Cognitive andMolecular Research Institute of Brain Diseases, Kurume University, Kurume; 3Department of Neurology,
Kida Hospital, Shimabara; 4Department of Bioscience and Bioinformatics, Faculty of Computer
Science and Systems Engineering, Kyushu Institute of Technology, Iizuka; 5PRESTO, Japan Scienceand Technology Agency, Kawaguchi, Saitama; 6Department of Pediatrics and Child Health, Kurume
University school of Medicine, Kurume, Japan
1

Abstract
Objective: Cervical dystonia (CD) is a clinically under-recognized symptom occurring at the later- to
end-stages of Parkinson’s disease (PD). The frequency of CD and its influence on prognosis havenot been well studied. Here, we conducted an in-depth examination of CD incidence and impact on
disease progression in later-stage PD. Methods: We retrospectively reviewed the clinical features of 22
deceased patients with sporadic PD treated at a hospital in Japan from 1983 to 2008. Results: The mostcommon cause of death in PD was pneumonia. CD, in particular retrocollis, was frequent in the laterstages of the disease in elderly patients (9/22, 40.9%). Pneumonia incidence increased sharply in thelater period with CD. There was a positive trend between CD duration and duration of pergolide use.
Conclusion: Analysis revealed that CD increases markedly in late- to end-stage PD, which may be
associated with aspiration pneumonia due to dysphagia. Pathological mechanisms underlying CD might
be influenced by treatments including dopamine agonists. Prevention of CD may increase quality oflife and prolong survival of PD patients.
Keywords: Parkinson’s disease, cervical dystonia, retrocollis, dopamine agonist, pneumonia
INTRODUCTION
Cervical dystonia (CD) is occasionally observed
in Parkinson’s disease (PD) and, at its later stages,
is associated with reduced quality of life and poor
prognosis due to dysphagia. However, there has
been little research on the frequency and formof CD in PD patients1–3, nor have there been
any reports on the influence of CD on diseaseprognosis or cause of death in patients with PD.
To address this research gap, we evaluated theclinical features of later-stage PD to clarify CD
incidence, risk factors, and role in PD progression.
METHODS
Consecutively deceased PD patients hospitalized
at the Kida Hospital, a private neurologicalinstitution in Japan, from January 1983 to
December 2008 were enrolled retrospectively.

All patients who fulfilled the UK Parkinson’s
Disease Society Brain Bank Clinical Diagnostic
Criteria4 received a neurological examination
by one of the authors. Patients with PD who
died at home or were transferred to a different
hospital were excluded. Twenty-two PD cases
were recruited. Clinical records were reviewed
for patient background (sex, age at onset, disease
duration, age at death, cause of death, and Hoehn
and Yahr [H&Y] Staging just before death) andtreatment (maximum dose of levodopa, maximum
dose of levodopa equivalent dose [LED] 5,
dopamine agonist type, duration of administrationof dopamine agonist, and stereoencephalotomy[functional neurosurgical procedure]). We divided
patients into two groups based on presence/absenceof CD (termed CD(+) and CD(−) groups). CD was
defined as neck extension/flexion accompanied
by enhanced muscle tone or spasm. There wereAddress correspondence to: Shiroh Miura, MD, PhD, Division of Respirology, Neurology and Rheumatology, Department of Medicine, Kurume University
School of Medicine, 67 Asahi-machi, Kurume City, Fukuoka Prefecture, 830-0011, Japan. Tel: +81-942-31-7560, E-mail: shiroh46@med.kurume-u.ac.jp245

Neurology Asianine and 13 cases of presence and absence ofCD, respectively. Both groups were comparedfor background and surgical treatment variables.
Furthermore, the frequency of pneumonia wascompared between the period with CD of ninecases and the period without CD of all 22 cases.
To evaluate groups’ differences, Fisher’s exact
test was used for sex ratio and proportion ofpatients receiving stereoencephalotomy; Welch’s
two-sample t-test for age at onset, age at death,disease duration, maximum dose of levodopa,
maximum dose of LED, cause of death, anddifference in frequency of pneumonia episode;and Wilcoxon rank-sum test (Mann–Whitney Utest) for H&Y Staging at death. The correlation
between duration of drug exposure of each
dopamine agonist and CD duration of all 22 cases
was examined by Spearman’s rank correlation
test.
We represented each patient by a multivariate
profile (a high-dimensional feature vector), in
which each element corresponds to a feature of
the patient, and constructed a multivariate dataset.
The profiles are based on 11 features: disease
duration, CD(+) duration, death by pneumonia,
maximum dose of levodopa, maximum doseof LED, bromocriptine, pergolide, cabergoline,
pramipexole, stereoencephalotomy, and H&Y
Staging at death. Each feature was normalized
scaled such that the average is zero and the standard
deviation is one. To analyze the relationships
among these features, we performed principal
component analysis (PCA). The goal of PCA
is to reduce the dimensionality of multivariate
data for easier interpretation by identifying a
few meaningful latent components. All statisticalanalyses in this study were conducted using thefree R statistical software package (http://www.rproject.org).
RESULTSWe recruited 22 PD cases (Table 1) andsummarized their background and treatment
information (Table 2). There were no differences
in sex ratio, age at onset, age at death, or H&Y
stage at death between the CD(+) and CD(−)
groups. Of the nine cases with CD (40.9%), eight
showed retrocollis (RC), one showed antecollis,
and no cases showed laterocollis. Age at onset
was younger in CD(+) patients, although thedifference did not reach statistical significance.
PD duration was significantly longer for CD(+)
patients (15.0 ± 2.2 years vs. 9.4 ± 1.1 years, p= 0.039). Regarding treatment, maximum dose

246

September 2018of levodopa was significantly higher for CD(+)
patients (433 ± 163 mg/day vs. 236 ± 126 mg/
day, p = 0.009), and the maximum dose of LED
tended to be higher for CD(+) patients. There
was a correlation between CD duration andduration of exposure to dopamine agonists (p= 0.001, r = 0.628), especially pergolide (p =0.009, r = 0.539). The average CD duration of
all 22 cases was 1.2 ± 0.4 years. The cases that
underwent longer treatment by dopamine agonists
had a longer CD duration. Four cases received
stereoencephalotomy, including one CD(−) case.
One case (Case No. 18) that received deep brain
stimulation in the bilateral globus pallidus internus
showed increased cervical rigidity within one
month and RC by the third postoperative month.
Pneumonia was the most common cause ofdeath (13 cases, 59%) (Figure 1A). Other causesof death were malignant tumor (four cases), acuteheart failure (two cases), malignant syndrome(two cases), and asphyxiation (one case). The
cause of death differed between groups, with ahigher proportion of CD(+) patients succumbing
to pneumonia (77.8% vs. 46.2%, p = 0.069),
although the difference did not reach statisticalsignificance. In nine cases, CD occurred at 13.0
± 2.1 years from PD onset and remained at death(Figure 1B). The frequency of pneumonia episodes
was significantly higher during the period withCD than the period without CD (0.314 ± 0.211
times/year vs. 0.070 ± 0.067 times/year, p = 0.004)(Figure 1C). The scatter-plot of scores for the firstand second principal components representing
the relations among the nine features of all 22
patients reveals possible positive relationships
between CD duration and lengths of pergolideand cabergoline use (Figure 1D, E).
DISCUSSION
The average age at death in our study population
was consistent with the average lifespan of
the general Japanese population (Ministry of
Health, Labour and Welfare, http://www.mhlw.
go.jp /english/database/db-hss/shw-index.html).
However, the causes of death were quite different,with pneumonia accounting for about 60% of PD
deaths compared to just 9.40% for the general
Japanese population (Ministry of Health, Labourand Welfare, http://www.mhlw.go.jp/english/
database/db-hh/index.html). As many of the latestage patients in this study were bedridden duringhospitalization, we speculate that they were more
susceptible to aspiration pneumonia6, as reported
by previous studies.7

247

Sex

F

F

F

M

F

M

F

F

F

M

F

F

M

Case No.

1

2

3

4

5

6

7

8

9

10

11

12

13

73

54

60

64

63

84

68

77

81

73

76

71

77

Onset age
(y.o)

87

67

73

75

74

93

77

84

88

79

81

74

78

Death age(y.o)

Table 1: Summary of cases

15

14

14

12

12

10

10

8

8

7

6

4

2

Diseaseduration
(y)

5

5

5

4

5

5

5

4

5

5

5

3

5

H&Y
stagingat death

458.3

150

-

Selegiline(2.5; 74)

Amantadine(150; 60–73)

Bromocriptine(10; 74−78)
Bromocriptine(7.5; 81−82)-

Bromocriptine(22.5; 70−74)
Bromocriptine(5; 67−68, 69,
70−72)
Cabergoline(2; 68−69)
Pramipexole(1.25; 72−74)

L/C(400; 73–79)
L/C(200; 80–89)
L/C(300; 78–81,
82–84)
L/C(250; 74–77)
L/B(200; 89–93)
L/C(300; 66–74)
L/B(300; 73–74)

L/B(300; 68–75)

Appendiceal
cancerHeart failure
Pneumonia,
DIC
Pneumonia
Metastatic
cancerAmantadine(150; 63–67)
Amantadine(150; 79–82,
84–85)-

Bromocriptine(7.5; 78−83)
Pergolide(1; 83−85)

L/C(300; 73–77)

L/C(300; 78–87)

Pneumonia

Malignantsyndrome, DIC

-

-

-

-

-

-

Amantadine(300; 72–73)-

Pneumonia

Lung cancer

Pneumonia

Pneumonia

Bromocriptine(7.5; 73)

L/C
(200; 72–73)

550

450

825

200

250

375

200

500

-

575

350

Heart failure

Amantadine(150; 77)-

L/C
(200; 77–78)

Maximum doseof LED(mg/day)

Malignantmelanoma

Other Drugs(Max dose (mg)
; Age of use(y.o))

L-dopa/DCI(Max dose (mg)
; Age of use (y.o))Cause of death
Dopamine agonist(Max dose (mg)
; Age of use (y.o))Treatment

-

-

Rt.
stereoencephalotomy
(54)

-

-

-

-

-

-

-

-

-

-

-

-

CD

-

-

-

-

-

-

-

-

-

-

-

Stereoencephalotomy
Age of operation (y.o)

15

14

14

12

12

10

10

8

8

7

6

4

2

CD (−)
duration
(y)

0

0

0

0

0

0

0

0

0

0

0

0

0

CD (+)
duration(y)

Feature of CD

0

2

1

0

1

0

2

3

2

1

0

1

1

CD (−)
period(times)

-

-

-

-

-

-

-

-

-

-

-

-

-

CD (+)
period(times)Frequencyof pneumonia

248

M

M

F

F

F

M

M

M

M

14

15

16

17

18

19

20

21

22

80

50

46

66

64

61

74

68

83

Onset age
(y.o)

95

74

70

81

77

73

83

77

88

Death age
(y.o)

16

25

25

16

14

13

10

10

6

5

5

5

5

5

5

5

5

5

H&Y
stagingat death

562.5

1083.3-

Amantadine(150; 70,
72–75)
Selegiline(5; 70, 72,
74–75)
Selegiline(5; 79–81)

Amantadine(300; 46)-

Bromocriptine(5; 77−79, 80−82)
Bromocriptine(11.25; 67−72)

Cabergoline(5; 70−75)
Pergolide(1.5; 72−75)

Pergolide(0.75; 79−80)
Pergolide(0.25; 67)
Bromocriptine(15; 67–69)
Bromocriptine(5; 66–72)
Pergolide(0.5; 72−74)
Cabergoline(5; 86−95)

L/C(250; 79–83)
L/B(450; 67–72)
L/C(500; 72–73)
L/C(600; 64–70)
L/B(300; 70–77)
L/C(500; 66–79)
L/B(400; 79–81)
L/C(600; 46–69)

L/B(600; 66–73)
L/B(400; 85–95)

Pneumonia

Pneumonia,
DIC

Malignant syndrome, DIC

Pneumonia

Asphyxiation

Pneumonia

Pneumonia

Amantadine(100; 85–95)

Amantadine(100; 75–79)

Amantadine(150; 77)

Bromocriptine(7.5; 71−74)
Pergolide(0.75; 74−77)

L/C(400; 69–77)

Pneumonia

833.3

650

1050

625

450

625

275

-

Pneumonia

Pergolide(0.75; 83−88)

Maximum doseof LED(mg/day)

L/C(200; 85–88)

Other Drugs(Max dose (mg)
; Age of use(y.o))

Dopamine agonist(Max dose (mg)
; Age of use (y.o))L-dopa/DCI(Max dose (mg)
; Age of use (y.o))Cause of death

Treatment-

Lt. thalamotomy (52)

Lt.
stereoencephalotomy(46)-

Bil. Gpi-DBS (75)

-

-

-

-

Stereoencephalotomy
Age of operation (y.o)

AC

RC

RC

RC

RC

RC

RC

RC

RC

CD

10

21

23

13

11

11

7

8

4

CD (−)
duration
(y)

6

4

2

3

3

2

3

2

2

CD (+)
duration(y)

Feature of CD

0

3

1

0

1

1

0

2

0

CD (−)
period(times)

4

7

1

1

2

2

1

3

1

CD (+)
period(times)Frequencyof pneumonia

CD, Cervical Dystonia; DIC, disseminated intravascular coagulation; RC, Retrocollis; AC, Antecollis; DCI, dopa-decarboxylase inhibitor; L/B, Levodopa/Benserazide; L/C, Levodopa/
Carbidopa; H&Y Staging on death; Hoehn & Yahr Staging just before clinical event of death; LED, levodopa equivalent dose

Sex

Case No.

Diseaseduration(y)

Neurology Asia
September 2018

Table 2: Analysis of background and treatment based on presence of CD
BackgroundTotal(n = 22)

CD (−)(n = 13)

CD (+) (n = 9)
(RC: AC = 8:1)

P valueCD (−) vs. CD (+)

Sex
(M:F)

10:12

4:9

6:3

p=1
(Fisher’s exact test)

Age at onset(y.o)

68.2 ± 2.2

70.8 ± 2.4

65.8 ± 4.1

p = 0.309(Welch’s two-sample t-test)

Age at death(y.o)

79.5 ± 1.6

79.2 ± 2.0

79.8 ± 2.6

p = 0.870(Welch’s two-sample t-test)

Disease duration(y)11.7 ± 1.2

9.4 ± 1.1

15.0 ± 2.2

p = 0.039(Welch’s two-sample t-test)

H&Y
Staging on death

4.8 ± 0.1

4.7 ± 0.2

5.0 ± 0.0

p = 0.145(Wilcoxon rank-sum test)

Internal treatment<L-Dopa/DCI>
Total(n = 22)

CD (−)(n = 13)

CD (+) (n = 9)
(RC: AC = 8:1)

P valueCD (−) vs. CD (+)

Maximum dose of levodopa(mg L-dopa/day)

318 ± 170

238 ± 126433 ± 163

p = 0.009(Welch’s two-sample t-test)

Maximum dose of LED(mg/day)

501 ± 279404 ± 224

641 ± 302

p = 0.064(Welch’s two-sample t-test)

Duration of medication
with dopamine agonists(n = 22)

CD duration(n = 22)

P value, correlation coefficient(Spearman’s rank correlation test)<Dopamine agonist>

4.3 ± 0.9

p = 0.001, r = 0.628

Bromocriptine (y)2.3 ± 0.6

p = 0.541, r = 0.137

Pergolide (y)1.0 ± 0.4

Cabergoline (y)0.8 ± 0.5

p = 0.111, r = 0.348

Pramipexol (y)0.1 ± 0.1

p = 0.437, r = −0.174

Breakdownof dopamineagonists

Total Dopamine agonist (y)1.2 ± 0.4

p = 0.009, r = 0.539

Surgical treatment

Stereoencephalotomy(cases)Total(n = 22)

CD (−)(n = 13)

CD (+) (n = 9)
(RC: AC = 8:1)

P valueCD (−) vs. CD (+)

41

3 (3:0)p = 0.2643(Fisher’s exact test for Count
Data)

CD, cervical dystonia; RC, Retrocollis; AC, Antecollis; DCI, dopa-decarboxylase inhibitor; H&Y, Hoehn & Yahr; LED,
levodopa equivalent dose249

Neurology Asia

September 2018

Figure 1. Clinical manifestation of PD. (A) Comparison of cause of death between patients with and without CD(cases, %). (B) Clinical course of all patients. (C) Frequency of pneumonia episodes in patients withCD (mean ± SD/years). (D) Scatter-plot of the first and second principal component scores derived
from PCA for the multivariate data of 22 patients. Each number corresponds to the index number of one
patient. (E) Scatter-plot of the first and second principal component weights derived from PCA for themultivariate data of 22 patients. Correlated features are located in proximity (CD(+) duration, durationof pergolide use, and duration of cabergoline use).
H&Y, Hoehn & Yahr; LED, levodopa equivalent dose250

A contributory factor of death by pneumonia
might be CD in later periods. A higher death rate
due to pneumonia was observed in patients with
CD despite no difference in age or PD severity
at death between patients with and without CD.
Indeed, frequency of non-lethal pneumonia
episodes increased sharply in later-stage CD.
Cervical hyperextension causes mechanicalchanges and affects aspiration even in healthy
subjects.8 Thus, these pneumonia cases may be due
to swallowing difficulties secondary to abnormal
cervical position, which can favor inhalation.
Of the few studies on CD in PD patients,
most have reported incidence of antecollis.1,2
Only one study found that advanced PD patientswith long disease duration had more frequently
RC3, consistent with our results. In this study,
the average disease duration was significantly
longer and the age at onset tended to be younger
in PD patients with CD. Whereas patients without
CD died around 10 years after PD onset, CD
generally developed after 10 years, suggestingthat the risk of CD increases progressively
with longer PD duration. Although the reason
for the high incidence of CD is unknown, it
is speculated that dystonia may arise from
dysfunction of the striosomal pathway9, i.e., thecircuit between substantia nigra and striosomes inthe striatum. In their study of X-linked recessive
dystonia-parkinsonism (XDP), Goto et al. (2005)
proposed that a hyperkinetic state resulting
from predominant impairment of the striosomal
pathway compared to the direct pathway inearly-stage PD causes dystonia and, as basal
ganglia dysfunction gradually extends to otherpathways, dystonia is replaced by Parkinsonism.10
In contrast to XDP, we speculate that progression
from direct pathway dysfunction in the earlystage of PD to dysfunction in the indirect andstriosomal pathways occurs in the transition fromhypokinetic symptoms to dystonia, particularly inneck muscles, during the later period.
Several PD treatments have been reported toexacerbate or mitigate CD.11,12 In this study, themaximum dose of levodopa differed significantly
between CD(−) and CD(+) patients. Moreover,associations between CD duration and length ofpergolide and cabergoline use were suggested
by PCA. Perhaps these treatments are involvedin CD development by differential influences on
direct, indirect, and striosome circuits.
In conclusion, aging PD patients appear
predisposed to CD, in particular RC. CD may
interfere with swallowing function, leading toaspiration pneumonia, a common cause of deathin PD. Pathological mechanisms underlying CD
might be influenced by levodopa and dopamineagonists. Prevention of CD may increase qualityof life and extend survival of PD patients.
DISCLOSURE
Financial support: This work is supported by JST
PRESTO [Grant Number JPMJPR15D8].
Conflict of interest: None
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