Movement Disorders

Vol. 25, No. 11, 2010, pp. 17441752

2010 Movement Disorder Society

Brief Reports

Abnormal Cardiac [123I]Meta-Iodobenzylguanidine Uptake

in Multiple System Atrophy

Multiple system atrophy (MSA) is characterized by

parkinsonism, cerebellar ataxia, autonomic failure, and
pyramidal signs in any combination as its main features. However, differential clinical diagnosis between
MSA and Parkinson disease (PD) is occasionally difcult, especially in the early stages, owing to several
overlapping features.1
Recently, myocardial scintigraphy using [123I]-metaiodobenzylguanidine (MIBG) has been used for the
assessment of parkinsonism. Myocardial MIBG uptake
is reportedly reduced in nearly all PD patients, whereas
it is relatively preserved in most patients with MSA.24
These ndings suggest that MIBG myocardial scintigraphy is useful in distinguishing patients with MSA
from patients with PD. However, several studies have
found a low myocardial MIBG uptake in a few patients
with MSA, suggesting that the uptake is not always
preserved in the disorder.24 The mechanisms underlying low MIBG uptake in some patients with MSA
remain controversial; however, secondary transsynaptic
distraction of postganglionic sympathetic nerves has
been considered to cause low MIBG uptake in MSA.3,4
Although these ndings suggest a possible change in
myocardial MIBG uptake with disease progression of
MSA, no study has reported a correlation between
myocardial MIBG uptake and disease severity.
In this study, we performed MIBG myocardial scintigraphy in a relatively large population with MSA.
Furthermore, longitudinal patient follow-up was also
carried out to determine the association between myocardial MIBG uptake and clinical features.

Hiroshi Nagayama, MD,* Masayuki Ueda, MD,

Mineo Yamazaki, MD, Yasuhiro Nishiyama, MD,
Makoto Hamamoto, MD, and Yasuo Katayama, MD
Divisions of Neurology, Nephrology, and Rheumatology,
Department of Internal Medicine, Nippon Medical School,
Tokyo, Japan
Abstract: [123I]-Meta-iodobenzylguanidine (MIBG) myocardial scintigraphy is useful for distinguishing multiple
system atrophy (MSA) from Parkinson disease. In this
study, longitudinal observation using MIBG myocardial
scintigraphy was carried out in patients with MSA to
evaluate the association of myocardial MIBG uptake with
clinical features. A total of 96 MIBG examinations were
performed in 52 patients with MSA. The heart/mediastinum (H/M) ratio of MIBG uptake at 240 minutes after
injection was below the lower limit in 16 patients with
MSA (31.3%). Overall, the H/M ratio correlated with neither disease duration nor severity. In the follow-up observations, the H/M ratio did not show any specic trends, in
contrast with the continuous decrease observed in
patients with Parkinsons disease. This data clearly
showed that cardiac MIBG uptake cannot necessarily be
preserved in patients with MSA and that approximately
30% of patients with MSA showed decreased MIBG
uptake without any correlation to disease duration or
severity. 2010 Movement Disorder Society
Key words: MIBG; myocardial scintigraphy; multiple
system atrophy

PATIENTS AND METHODS

Patients
Of the consecutive patients who were admitted to
our clinical service between May 1998 and December
2007, 56 patients fullled the criteria for probable
MSA during their follow-up periods.5 These 56
patients underwent single photon-emission computed
tomography and brain magnetic resonance imaging to
conrm that their neuroradiologic features were consistent with those of MSA. None of these patients had
any conditions known to interfere with MIBG
uptake.6,7 Four patients were excluded from the study

*Correspondence to: Dr. Hiroshi Nagayama, Divisions of Neurology, Nephrology, and Rheumatology, Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi Bunkyo-ku, Tokyo 1138603, Japan. E-mail: nagayama@nms.ac.jp
Potential conict of interest: All authors have no nancial disclosure or conicts of interest related to this article.
Received 22 November 2009; Revised 6 March 2010; Accepted 9
June 2010
Published online 19 July 2010 in Wiley InterScience (www.
interscience.wiley.com). DOI: 10.1002/mds.23338

1744

ABNORMAL CARDIAC MIBG UPTAKE IN MSA

because of cardiac disorders. The remaining 52 patients
were enrolled in this study, and longitudinal follow-up
was initiated.

MIBG Myocardial Scintigraphy and Data Analysis

During the study period, MIBG myocardial scintigraphy was performed 96 times in the 52 patients. To
determine the normal range of the heart/mediastinum
(H/M) ratio, data from 10 normal controls of similar
age were used. MIBG myocardial scintigraphy was
carried out at least twice in 25 patients. Informed consent was obtained from each person, and the approval
of the institutional review board was obtained. Data
were collected for 180 seconds at 240 minutes after
injection of 111 MBq of [123I] MIBG (Daiichi Radioisotope Laboratories, Tokyo, Japan) by using a dualhead gamma camera GCA-602A (Toshiba Medical,
Tokyo, Japan), and a static image was obtained with a
128 3 128 matrix. Regions of interest (ROIs) were
manually drawn around the heart and mediastinum,
and the tracer uptake was measured within each ROI
to calculate the H/M ratio.
The prevalence of decreased H/M ratio and the correlation between the H/M ratio and clinical parameters
were examined; the differences in the H/M ratio
between the MSA subgroups [parkinsonism-predominant MSA (MSA-P) and cerebellar ataxia-predominant
MSA (MSA-C)]1 were also analyzed. In one of the
clinical parameters, disease severity was classied into
ve stages in accordance with the Global Disability
Scale (GDS) described in the Unied Multiple System
Atrophy Rating Scale (UMSARS).8 This classication
was performed retrospectively on the basis of medical
records of 58 scintigraphies performed before 2004
because UMSARS was not available at the time
of examinations. Furthermore, temporal changes in the
H/M ratio were evaluated in the 25 patients for whom
MIBG myocardial scintigraphy was performed more
than once.

Statistical Analysis
Statistical analysis was performed using StatView
version 5.0 on a Macintosh computer. The v2 test,
Kruskal-Wallis rank test, Mann-Whitney U test, Spearmans rank correlation, Pearsons correlation coefcient, and paired t test were used for analysis, wherever applicable. Values were expressed as mean 6 SD,
and statistical signicance was set at P < 0.05.

1745
RESULTS

Normal Range of H/M Ratio and Analysis of All

96 Examinations
Focal defects in myocardial MIBG uptake were not
observed in patients or controls. The average age at
the time of 96 examinations in patients with MSA and
10 examinations in controls was 65.4 6 6.4 and 66.3
6 6.0 years, respectively. Average disease duration at
the time of examinations in patients with MSA was
41.6 6 26.8 months. No statistically signicant differences were found in age between the controls and
patients with MSA (P 5 0.73).
The mean H/M ratio in control subjects was 2.06 6
0.15, and the lower normal limit was set at 1.76. In
patients with MSA, the mean H/M ratio was 1.93 6
0.39. According to the cutoff line, H/M ratios in
patients with MSA were decreased in 30 examinations
(31.3%) and were normal in 66 (68.7%). Between
patients with normal and decreased H/M ratios, no statistically signicant differences were observed in the
age (65.8 6 6.8 versus 64.7 6 5.6 years, P 5 0.670)
and disease duration (39.6 6 23.3 versus 46.1 6 33.3
months, P 5 0.531).
There were no statistically signicant differences in
age among the GDS stages (P 5 0.972). The mean H/
M ratios of GDS 1 to GDS 5 were found to be 2.00 6
0.38, 1.97 6 0.39, 1.91 6 0.35, 1.89 6 0.47, and 1.91
6 0.43, respectively. No correlation was found
between disease severity and H/M ratio (P 5 0.31).
All patients were classied into two MSA subgroups: 44 patients (78 examinations) were classied
as MSA-C and 8 patients (18 examinations), as MSAP. There were no signicant differences in disease duration, disease severity, and age between the subgroups
(P 5 0.069, 0.22, and 0.97, respectively). Mean H/M
ratios in the MSA-C and MSA-P groups were 1.98 6
0.39 and 1.74 6 0.35, respectively (Fig. 1). This difference in means between the subgroups was statistically signicant (P 5 0.016).
Analysis of 25 Longitudinally Followed Up Patients
Twenty-ve patients underwent MIBG myocardial
scintigraphy more than once (69 examinations; 2.8 6
1.3 times): 19 MSA-C patients and 6 MSA-P patients
(53 and 16 examinations, respectively). The temporal
changes in H/M ratio are shown in Figure 2. To evaluate whether temporal changes in H/M ratio have a
particular tendency, the changes in H/M ratios
between successive examinations were analyzed.
However, the temporal change in H/M ratio did not

Movement Disorders, Vol. 25, No. 11, 2010

1746

H. NAGAYAMA ET AL.

FIG. 1. Heart/mediastinum (H/M) ratio in each subgroup. The box

plots show the median values (centerline of box) and the 25th (lower
line of box), 75th (upper line of box), 10th (lower T bar), and 90th
percentile (upper T bar) in each group. The cutoff line is 1.76 and
indicates 2 SD below the control mean. MSA-P, multiple system atrophy (parkinsonism predominant); MSA-C, multiple system atrophy
(cerebellar ataxia predominant).

Recent studies have shown pathologic changes

within sympathetic ganglia in several patients with
MSA.1012 These changes may explain the reduced
myocardial MIBG uptake in several patients with
MSA. Sone et al.11 reported alpha-synuclein-immunoreactive structures, including Lewy bodies (LBs) and
LB-like structures, within the neuronal cytoplasm and
processes of the sympathetic ganglia in 42.3% of
patients with MSA. Degeneration of cardiac sympathetic nerves may precede loss of dorsal vagal neurons
in incidental LB disease;13 therefore, ganglionic LBs
may progress to central neurodegeneration. Furthermore, cardiac sympathetic lesions, possibly related to
LB pathology to some extent, may be present in 46.7%
of patients with MSA.10 This prevalence is slightly
higher than that of low myocardial MIBG uptake (20
30%) in patients with MSA; however, the pathologically detected cardiac sympathetic changes include
prestage LB formation.11 This difference suggests that
the prevalence of low myocardial MIBG uptake may

show a signicant tendency in patients with MSA-C

and MSA-P as well as all the 25 patients (P 5 0.93,
0.72, and 0.42, respectively).
DISCUSSION
This study showed that one third of patients with
MSA had low cardiac MIBG uptake. This result is similar to that of our previous trial (21%).2 These ndings
indicate that 2030% of patients with MSA may have
myocardial sympathetic dysfunction to some extent.
The precise mechanisms underlying low cardiac
MIBG uptake in MSA patients remain unclear. Because
autonomic dysfunction in MSA is thought to result from
sympathetic preganglionic lesions,1 secondary transsynaptic distraction of postganglionic sympathetic nerves
may cause the low MIBG uptake detected in some
patients with MSA. However, no correlation between H/
M ratio and disease severity was observed in this study.
Furthermore, myocardial uptake of [18F]-uorodopamine
is reportedly preserved regardless of the presence of
dysautonomia in patients with MSA.9 Therefore, secondary postganglionic sympathetic degeneration cannot
explain the reduced MIBG uptake in patients with
MSA. In addition, because the H/M ratio did not show
any specic temporal trends, disease progression may
not affect the H/M ratio in MSA.

Movement Disorders, Vol. 25, No. 11, 2010

FIG. 2. Time course change in the heart/mediastinum (H/M) ratio in

25 patients who underwent MIBG myocardial scintigraphy more than
once. The cutoff line is 1.76 and indicates 2 SD below the control
mean. MSA-C, multiple system atrophy (cerebellar ataxia predominant); MSA-P, multiple system atrophy (parkinsonism predominant);
M, months.

ABNORMAL CARDIAC MIBG UPTAKE IN MSA

reect the presence of mature LB pathology because
disorders with the presence of LBs are related to low
cardiac MIBG uptake.14 We recently reported an
autopsied patient with MSA showing low cardiac
MIBG uptake with an incidental LB pathology in addition to a typical MSA pathology.15 Therefore, the presence of LB pathology may be a suitable explanation
for the low myocardial MIBG uptake observed in
patients with MSA. This may also explain the signicantly lower H/M ratio in patients with MSA-P compared with that in patients with MSA-C observed in
this study if LB pathology as PD precedes MSA pathology in some cases with MSA-P.
In conclusion, although MIBG myocardial scintigraphy is known to be a valuable codiagnostic tool for
discriminating parkinsonian syndromes, interpretation
of this examination in patients with MSA requires
careful consideration.
Author Roles: 1. Research project: (A) Conception, (B)
Organization, (C) Execution. 2. Statistical Analysis: (A)
Design, (B) Execution, (C) Review and Critique. 3. Manuscript: (A) Writing of the rst draft, (B) Review and Critique.
Nagayama: 1A, 1C, 2A, 2B, 3A. Ueda: 1A, 1B, 3A, 3B.
Yamazaki: 1A, 1B, 3B. Nishiyama: 1C, 2B, 3B. Hamamoto:
1A, 3B. Katayama: 1A, 3C.

1747

7. Braune S. The role of cardiac metaiodobenzylguanidine uptake

in the differential diagnosis of parkinsonian syndromes. Clin
Auton Res 2001;11:351355.
8. Wenning GK, Tison F, Seppi K, Sampaio C, Diem A, Yekhlef
F, et al. Development and validation of the Unied Multiple
System Atrophy Rating Scale (UMSARS). Mov Disord
2004;19:13911402.
9. Goldstein DS, Holmes C, Li S, Bruce S, Metman LV, Cannon
III RO. Cardiac sympathetic denervation in Parkinson disease.
Ann Intern Med 2000;133:338347.
10. Orimo S, Kanazawa T, Nakamura A, et al. Degeneration of cardiac sympathetic nerve can occur in multiple system atrophy.
Acta Neuropathol 2007;113:8186.
11. Sone M, Yoshida M, Hashizume Y, Hishikawa N, Sobue G.
Alpha-synuclein-immunoreactive structure formation is enhanced
in sympathetic ganglia of patients with multiple system atrophy.
Acta Neuropathol 2005;110:1926.
12. Nishie M, Mori F, Fujiwara H, et al. Accumulation of phosphorylated alpha-synuclein in the brain and peripheral ganglia of
patients with multiple system atrophy. Acta Neuropathol
2004;107:292298.
13. Orimo S, Takahashi A, Uchihara T, Mori F, Kakita A, Wakabayashi K, Takahashi H. Degeneration of cardiac sympathetic
nerve begins in the early disease process of Parkinsons disease.
Brain Pathol 2007;17:2430.
14. Watanabe H, Ieda T, Katayama T, et al. Cardiac (123) I-metaiodobenzylguanidine (MIBG) uptake in dementia with Lewy
bodies: comparison with Alzheimers disease. J Neurol Neurosurg Psychiatry 2001;70:781783.
15. Nagayama H, Yamazaki M, Ueda M, et al. Low myocardial
MIBG uptake in multiple system atrophy with incidental Lewy
body pathology: an autopsy case report. Mov Disord 2008;23:
10551057.

Financial Disclosures: M. Yamazaki: Grant-in-Aid for

Scientic Research (#20591034 and #22300117) from the
Ministry of Ministry of Education, Science, Culture, Sports
and Science, Japan. Y. Nishiyama: Grant-in-Aid for Young
Scientists (#20790628) from the Ministry of Education, Science, Culture, Sports and Science, Japan; Received research
funding from Akaeda medical research foundation. M. Ueda
and Y. Katayama: Grant-in-Aid for Scientic Research
(#20591011) from the Ministry of Education, Science, Culture, Sports and Science, Japan.

REFERENCES
1. Wenning GK, Colosimo C, Geser F, Poewe W. Multiple system
atrophy. Lancet Neurol 2004;3:93103.
2. Nagayama H, Hamamoto M, Ueda M, Nagashima J, Katayama
Y. Reliability of MIBG myocardial scintigraphy in the diagnosis
of Parkinsons disease. J Neurol Neurosurg Psychiatry
2005;76:249251.
3. Yoshita M. Differentiation of idiopathic Parkinsons disease from
striatonigral degeneration and progressive supranuclear palsy
using iodine-123 meta-iodobenzyl guanidine myocardial scintigraphy. J Neurol Sci 1998;155:67.
4. Druschky A, Hilz MJ, Platsch G, et al. Differentiation of Parkinson s disease and multiple system atrophy in early disease
stages by means of I-123-MIBG-SPECT. J Neurol Sci 2000;
175:312.
5. Gilman S, Low P, Quinn N, et al. Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci 1999;163:9498.
6. Kashihara K, Yamamoto M. Myocardial 123I-MIBG scintigraphy
in patients with PSP, CBD and MSA. J Neurol 2006;253(suppl
3):III/35III/40.

Movement Disorders, Vol. 25, No. 11, 2010

1748

P.P. URBAN ET AL.

Subacute Axonal Neuropathy in

Parkinsons Disease with
Cobalamin and Vitamin B6
Deciency Under Duodopa
Therapy
Peter P. Urban, MD, PhD, * Ingmar Wellach, MD,
Siegbert Faiss, MD, PhD,2 Peter Layer, MD, PhD,3
Thorsten Rosenkranz, MD,4 Karl Knop, MD,4 and
Joachim Weis, MD, PhD5
1

Department of Neurology, Asklepios Klinik Barmbek,

Hamburg, Germany; 2Department of Internal Medicine,
Gastroenterology, Asklepios Klinik Barmbek, Hamburg,
Germany; 3Department of Internal Medicine, Israelitisches
Krankenhaus, Hamburg, Germany; 4Department of
Neurology, Asklepios Klinik St.Georg, Hamburg, Germany;
5
Medical Faculty, Institute of Neuropathology, RWTH
Aachen University, Aachen, Germany
Abstract: We describe two patients who developed subacute axonal peripheral neuropathy under duodopa treatment. Comprehensive diagnostic workup including muscle
and sural nerve biopsy revealed that the most probable
cause of subacute axonal peripheral neuropathy was
cobalamin and vitamin B6 deciency in both the
patients. 2010 Movement Disorder Society
Key words: Parkinsons disease; duodopa; peripheral neuropathy; cobalamin; vitamin B6

Duodopa therapy is a useful treatment option in

patients suffering from Parkinsons disease (PD) with
severe motor uctuations, which do not respond satisfactorily to orally or transdermally applied drugs.1
However, a number of recent reports have described
the occurrence of acute peripheral neuropathy (PN)
under duodopa therapy. The neuropathy occurring in 1
patient 7 months after starting duodopa treatment was
classied as Guillain-Barre syndrome (GBS).2 One
patient of another recent study developed severe axonal
PN and reversible encephalopathy 5 months after duodopa initiation.3

*Correspondence to: Prof. Dr. Peter P. Urban, Department of Neurology, Asklepios Klinik Barmbek, Rubenkamp 220, 22291 Hamburg, Germany. E-mail: p.urban@asklepios.com

Potential conict of interest: Nothing to report.

Received 20 April 2010; Revised 20 May 2010; Accepted 15 June
2010
Published online in Wiley InterScience (www.interscience.wiley.
com). DOI: 10.1002/mds.23342

Movement Disorders, Vol. 25, No. 11, 2010

We describe two additional patients who developed

subacute axonal neuropathy under duodopa therapy.

CASE REPORTS
Patient #1
A 67-year-old man with a 5-year history of PD
developed severe motor uctuations with paroxysmal
freezing of long duration and pathologic gambling,
which did not respond sufciently to oral and/or transdermal dopaminergic therapy. Duodopa treatment was
started in 2008, and the patient responded very favorably regarding the motor disturbances; a considerable
improvement of the pathologic gambling was further
found. After 13 months of monotherapy with duodopa
(1 mL duodopa gel 5 20 mg Levodopa (L-Dopa);
base rate: 5 mL/hour, morning bolus: 13 mL; extra
bolus: 3 mL), the patient began to complain of painful
bilateral pins-and-needles paresthesias and numbness in
both feet and hands with increasing intensity during
the night. No prior infection was reported.
The clinical examination showed no ankle reexes,
a stocking distribution loss of pinprick and temperature
sensation, and a distal vibratory impairment but no
muscle weakness.
Nerve conduction studies (Table 1) were consistent
with mild axonal sensorimotor polyneuropathy. Needle
eletromyographic examination of the lower extremities
(tibial anterior muscles) showed mild signs of denervation with brillations and positive sharp waves. MUAP
analysis revealed an increased number of polyphasic
potentials (>20%), and maximum recruitment showed
a reduced number of potentials.
Blood tests (Table 2) revealed increased homocysteine (Hcy) and reduced holotranscobalamin (holoTC) levels, at normal cobalamin and methylmalonic
acid (MMA) concentrations. Vitamin B6 level was
reduced. CSF ndings were unremarkable. Anti-ganglioside IgM and IgG antibodies (GM1,2,3,4; GD1a,b;
GD2,3; GT1a,b; GQ1b; sulfatide) were negative. Furthermore, borrelia-antibodies, HSV-IgM, VZV-IgM,
HIV-antibodies, anti-hu, ANA, ENA, ANCA, immunoxation, and TPHA were negative. Diabetes mellitus was excluded; there was no history of alcohol
consumption. All other routine blood parameters were
within the normal range. No evidence of a paraneoplastic origin was detected (chest and abdomen CT
scan, gastroscopy, coloscopy). Gastroscopy showed a
mild chronic gastritis with helicobacter pylori. One
week eradication treatment with metronidazole and
clarithromycin was performed based on these ndings.

AXONAL NEUROPATHY UNDER DUODOPA THERAPY

1749

TABLE 1. Nerve conduction studies

Nerves
R median
R PTN
R DPN
R/L sural

Patient
#1
#2
#1
#2
#1
#2
#1
#2

MCV (m/s)
a

38.1
44.4
35.6a
40.6
37.6a
41.0

CMAP (mV)
5.4
5.8
1.1a
1.9a
1.0a
1.2a

DML (ms)
4.2
3.9
4.2
4.5
4.2
6.2

SCV (m/s)
a

SNAP (lV)
2.6a
3.0a

40.3
42.5

absenta
absenta

a
Abnormal ndings according to age-related normal values of our laboratory.
R: right, L: left, PTN: posterior tibial nerve, DPN: deep peroneal nerve, MCV: motor conduction velocity, CMAP: compound motor action
potential, DML: distal motor latency, SCV: sensory conduction velocity, SNAP: sensory nerve action potential.

The parietal cell and gliadin antibodies were negative.

Serum D-xylose test showed normal results.
Sural nerve and gastrocnemic muscle biopsy were
performed as described by Weis and Schroder,4 which
showed a neurogenic lesion pattern in the muscle and
an axonal neuropathy without signs of vasculitis or amyloidosis. A marked reduction in myelinated nerve
ber density and considerable endoneurial edema were
identied. Myelin debris was found in a number of
endoneurial macrophages, indicating recent nerve ber
breakdown. Inammatory inltrates of CD8-immunoreactive T-cells were absent (Fig. 1), as were indirect
signs of inammatory neuropathy such as focally
accentuated nerve bre loss.
Parenteral substitution for the management of a
functional cobalamin and vitamin B6 deciency was
then started. The polyneuropathy did not worsen and
was stabilized under continuous duodopa treatment
during a follow-up of 10 months.

Patient #2
A 76-year-old woman with a 23-year history of PD
received monotherapy with duodopa (1 mL duodopa gel
5 20 mg L-Dopa; base rate: 3.4 mL/hour, morning bolus:
7 mL; extra bolus: 3 mL) because of increasing motor
function uctuations in 2008. Thirteen months later she
developed increasing tingling and numbness in both feet
and hands with unsteadiness of gait and weakness of both
legs. The patient did not recall a preceding infection.
The clinical examination demonstrated no ankle
reexes, loss of pinprick and temperature sensation in a
stocking distribution, and distal vibratory loss with
impaired proprioception at the toes. The patient further
showed mild distal leg weakness and moderate gait ataxia.
Nerve conduction and electromyographic studies
(Table 1) were consistent with axonal sensorimotor
polyneuropathy.

Blood tests (Table 2) revealed increased homocysteine and methylmalonic acid levels. Holotranscobalamin was reduced, and cobalamin was normal. Vitamin
B6 level was reduced. CSF ndings were unremarkable.
Anti-ganglioside antibodies (s. patient #1) were negative, as well as borrelia antibodies, ANA, ENA, ANCA,
immunoxation, and TPHA testing. Diabetes mellitus
was excluded and no history of alcohol consumption.
All other routine blood parameters were within the normal range. No gastritis was found on gastroscopy.
Sural nerve and gastrocnemic muscle biopsy showed
a neurogenic lesion pattern in the muscle, and an axonal neuropathy without signs of vasculitis or amyloidosis. A marked reduction in myelinated nerve ber density and considerable endoneurial edema were present.
Myelin debris was found in several endoneurial macrophages, indicating recent nerve ber breakdown.
Inammatory inltrates of CD8-immunoreactive Tcells were absent (Fig. 1).
Parenteral substitution was started for the management of a functional cobalamin and vitamin B6 deciency. The polyneuropathy did not worsen and was
stabilized under continuous duodopa treatment during a
follow-up of 10 months.

TABLE 2. Laboratory data on serum vitamin levels

Patient #1 Patient #2 Normal range
Homocysteine (Hcy)
Methylmalonic acid (MMA)
Holotranscobalamin (holo-TC)
Vitamin B12 (cobalamin)
Vitamin B6 (pyridoxine)
Vitamin B1 (thiamine)
Vitamin B2 (riboavin)
Vitamin B3 (niacin)
Vitamin E (tocopherol)

19 :
295
36 ;
250
3;
58
230
50.3
9.3

35.8 :
798 :
26 ;
236
3.6 ;
82
208
n. t.
16.8

<12 lmol/L
50300 nmol/L
>50 pmol/L
191663 ng/L
>4.9 lg/L
2885 lg/l
157275 lg/L
852 lg/L
517 mg/L

:, increased; ;, decreased; n. t., not tested.

Movement Disorders, Vol. 25, No. 11, 2010

1750

P.P. URBAN ET AL.

FIG. 1. Nerve biopsies featuring severe, rapidly progressive axonal neuropathy in both cases (semithin sections, toluidine blue). (A) and (B):
patient #1; (C) and (D): patient #2 (A) and (C): Marked reduction in myelinated nerve ber density, axonal atrophy and considerable endoneurial
edema (arrows). Scale bars 5 60 lm. (B) and (D): At a higher magnication, myelin debris is found in several endoneurial macrophages (black
arrows), indicating recent nerve ber breakdown. Inammatory inltrates of CD8-immunoreactive T-cells were absent. White arrows: shrunken,
atrophic axons of myelinated nerve bers. Scale bars 5 30 lm

DISCUSSION
There is little evidence that PD in itself is associated
with PN. In a study of PD patients with a parkin gene
mutation, 1 of 24 patients had a sensory and autonomic
axonal neuropathy demonstrated both electrophysiologically and histopathologically by nerve biopsy.5 This
nding might be explained by the presence of parkin
in the peripheral nerve as well.6
An increase of Hcy plasma level is a known sideeffect of L-Dopa therapy (for details see Ref. 7, 8).
Although reduced amplitudes of sural nerve action
potentials indicating axonal sensory PN have been
reported in association with elevated Hcy-levels, clini-

Movement Disorders, Vol. 25, No. 11, 2010

cal neuropathy sum scores did not differ signicantly

between PD patients with normal and elevated Hcylevels.8 Furthermore, subacute development of PN as
present in our patients has not been mentioned in association with elevated Hcy-levels and normal cobalamin
and vitamin B6.8
In a prospective observational study, clinical and
electrophysiological data demonstrated the development of PN in 49 out of 500 patients with PD after the
initiation of L-dopa therapy.9 Furthermore, both in
patients with a probable etiology of the neuropathy (N
5 15) and without a dened etiology (N 5 34), mean
cobalamin levels were signicantly decreased. At the

AXONAL NEUROPATHY UNDER DUODOPA THERAPY

same time, a substantial increase in MMA-and Hcylevels compared to PD patients without PN and those
with idiopathic neuropathy was noted.8
A recent report described a patient who developed
severe axonal PN and reversible encephalopathy 5
months after duodopa initiation.3 The authors found a
slight cobalamin deciency (224 pg/mL; normal range:
200900 pg/mL) and a signicant increase in MMA
(0.22 lmol/L; normal value: <0.15lmol/L) and Hcy
(59 lmol/l; normal value: <15 lmol/L) plasma levels.
After discontinuation of duodopa therapy and start of
cobalamin supplementation, the paresis and mental deficits improved markedly. Although elevated Hcy and
MMA, as well as reduced holo-TC levels are regarded
as markers for cobalamin deciency, they are not
known to have any specic toxicity for the peripheral
nervous system by themselves.9,10
Antonini et al.2 described another patient who developed acute PN 7 months after initiation of duodopa
therapy. The possibility of GBS was hypothesized, but
plasmapheresis did not lead to a signicant improvement. Cobalamin and other vitamin levels were not
reported for this patient. In the patients of our study,
normal CSF ndings, the absence of antiganglioside
antibodies or previous infections, and no histological
abnormalities as indicators of polyneuritis render the
presence of an axonal variant of GBS (acute motor
axonal neuropathy) improbable.
A comprehensive diagnostic workup showed a deciency of cobalamin and vitamin B6 as the most probable etiology of subacute polyneuropathy in our
patients. The clinical syndrome of sensorimotor distal
symmetric and painful polyneuropathy is known in
patients with vitamin B6 deciency because of isoniazid treatment11 and cobalamin deciency.12 The electrodiagnostic pattern of axonal neuropathy conrmed
by sural nerve biopsy was further found in vitamin B6
and cobalamin deciency.13,14 The histological ndings
in our patients are, therefore, in line with an etiology
of malnutrition described by Thaisetthawatkul et al.15
The positive effects of cobalamin and vitamin B6 supplementation regarding the prevention of disease progression are in support of this assumption. Previous
studies on PD and PN do not include a discussion of
vitamin B6 levels. We, therefore, assume that the subacute axonal PN in our patients may be a consequence
of vitamin B6 deciency alone or in combination with
cobalamin deciency.
The mechanisms by which duodopa therapy might
inuence cobalamin or vitamin B6 levels are currently
not known. Duodopa is infused directly into the upper
jejunum, which has an important role in the absorption

1751

of vitamin B6 and cobalamin. This was conrmed by

reports of patients with bariatric surgery using a duodenal switch16 or gastrojejunal bypass1,5,17 who showed
vitamin B6 and cobalamin deciency with GBS-like
polyneuropathies. However, not all patients under duodopa therapy develop neuropathy, and it is not known
if a genetic susceptibility in PD patients might be a
risk factor for the development of PN under high-dose
L-dopa therapy.
From a clinical point of view, it may be advisable to
measure cobalamin, holo-TC, MMA, Hcy, and vitamin
B6 levels before starting duodopa therapy, and to monitor these parameters together with the clinical condition regarding the development of PN. This might clarify if elevated Hcy levels or a preexisting cobalamin
and/or vitamin B6 deciency increase the risk for PN
under duodopa treatment. It has to further be claried
if a prophylactic vitamin B complex therapy may prevent PN in patients receiving duodopa therapy, and if
this therapy is also advisable in PD patients with highdose oral L-dopa therapy. It is also still unknown if
duodopa therapy should be discontinued when an otherwise unexplainable PN occurs.
Financial Disclosures: Dr. Urban has received honoraria for advisory boards or speeches from Boehringer
Ingelheim, Desitin, Glaxo Smith Kline, Lundbeck,
Orion, Meda/Valeant, Teva, UCB-Schwarz-Pharma,
and Solvay. Dr. Wellach has received honoraria for
speeches from Desitin, Meda/Valeant, and Solvay. Dr.
Faiss has received grants from Fresenius, Fujinon,
Olympus, Biotechon, and Given Imaging; and honoraria for speeches from Falk Foundation e.V., Altana,
Nycomed, Roche, and Abbott. Dr. Rosenkranz has
received honoraria for speeches and advisory boards
from BiogenIdec, Merck Serono, Boehringer Ingelheim, Bayer Health Care, Aventis-Sano, Teva, and
Novartis. Dr. Knop has received honoraria for speeches
from Merck Serono and Biogen Idec. Dr. Weis
received grants from the Deutsche Forschungsgemeinschaft (DFG), EU EURON Marie Curie program,
Bundesministerium fur Bildung und Forschung MDNet, Robert Koch-Institut, Belgian Science Policy
IAP Attraction Pole program, Dr. med h.c. E. BraunStiftung, Basel, Switzerland, IZKF Aachen.
Author Roles: Urban PP was involved in study concept, design, and manuscript writing. Wellach I was
involved in care of the patients in the hospital setting
and management of the study. Faiss S and Layer P
were responsible for the gastroenterological aspects in
the article. Rosenkranz T and Knop C were involved

Movement Disorders, Vol. 25, No. 11, 2010

1752

P.P. URBAN ET AL.

in analyzing of the muscle biopsy. Weis J was

involved in analyzing of the sural nerve biopsy.

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