Movement Disorders
Vol. 24, No. 10, 2009, pp. 1519–1545
Ó 2009 Movement Disorder Society
Brief Reports
No Lewy Pathology in Monkeys
with Over 10 Years of Severe
MPTP Parkinsonism
In both Parkinson’s disease (PD) and the 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate
model, nigrostriatal dopaminergic neurons are more
selectively targeted than other brain regions, and dopaminergic replacement therapies give symptomatic
relief.1 However, a major difference between idiopathic
PD and MPTP-primate models is the extensive abnormal deposition of a-synuclein in the form of insoluble
neuronal Lewy bodies and neurites in PD but not in
this animal model.2 The recent identification of Lewy
bodies in human fetal transplants surviving 11–16
years suggests that such lesions accumulate over a decade,3 consistent with longitudinal postmortem studies.4
To determine whether this time frame is sufficient for
abnormal a-synuclein accumulation in the MPTP-primate model, two cynomolgus monkeys (Macaca fascicularis) were treated with MPTP and their brains
examined after 10 years of Parkinsonism.
Glenda Halliday, PhD,1* Maria Trinidad Herrero, MD,2
Karen Murphy, BSc (Hons),1
Heather McCann, BMedSci (Path),1
Francisco Ros-Bernal, BSc,2 Carlos Barcia, PhD,2
Hideo Mori, MD,3 Francisco J. Blesa, BSci,4
and José A. Obeso, MD4
1
Prince of Wales Medical Research Institute and School of
Medical Sciences, Faculty of Medicine
University of New South Wales, Sydney, Australia;
2
Experimental Neuroscience, Department of Anatomy, Medical School, University of Murcia and CIBERNED, Murcia,
Spain; 3Department of Neurology, Juntendo University
School of Medicine, Bunkyo-ku, Tokyo, Japan; 4Department
of Neurology and Neuroscience Division, Clinica
Universitaria and Medical School, Neuroscience Center,
CIMA and CIFA, University of Navarra and CIBERNED,
Pamplona, Spain
METHODS
Animals
Two 8-year-old control (Monkey 1 and 2) and two
14-year-old cynomolgus (Macaca fascicularis) monkeys, previously made parkinsonian at 2 years of age
with intermittent intravenous injections of 0.3 mg/kg
MPTP for 2 years (Monkey 3 and 4, see Table 1
and5,6), were sacrificed with a lethal pentobarbital
injection after ketamine anesthesia, their brains
removed and hemisected with one half (three right and
one left) fixed for 3 days in 4% paraformaldehyde dissolved in 0.1 M phosphate buffer and the other half
dissected, frozen in dry ice, and stored at 2808C. All
monkeys were from the same provider and were kept
under similar living conditions with all studies carried
out in accordance with the Declaration of Helsinki and
with the Guide for the Care and Use of Laboratory
Animals adopted and promulgated by the United States
National Institutes of Health and the European Union.
Abstract: The recent knowledge that 10 years after transplantation surviving human fetal neurons adopt the histopathology of Parkinson’s disease suggests that Lewy body
formation takes a decade to achieve. To determine
whether similar histopathology occurs in 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP)-primate models
over a similar timeframe, the brains of two adult monkeys made parkinsonian in their youth with intermittent
injections of MPTP were studied. Despite substantial nigral degeneration and increased a-synuclein immunoreactivity within surviving neurons, there was no evidence of
Lewy body formation. This suggests that MPTP-induced
oxidative stress and inflammation per se are not sufficient
for Lewy body formation, or Lewy bodies are human
specific. Ó 2009 Movement Disorder Society
Key words: a-synuclein; monkeys; MPTP; parkinsonism;
substantia nigra
*Correspondence to: Prof. Glenda Halliday, Prince of Wales Medical Research Institute, Barker Street, Randwick, NSW 2031, Australia. E-mail: g.halliday@powmri.edu.au
Potential conflict of interest: The authors have nothing to disclose.
Received 3 December 2008; Revised 6 January 2009; Accepted 14
January 2009
Published online 15 June 2009 in Wiley InterScience (www.
interscience.wiley.com). DOI: 10.1002/mds.22481
Histopathology
The fixed hemibrain was cut coronally, and the
brainstem and cerebellum were cut transversely at
2.5 mm. Samples were taken from superior frontal
1519
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G. HALLIDAY ET AL.
TABLE 1. Details of experimental age, symptoms, age at death, and neuropathological parameters
Macaque
M1
M2
M3
M4
Experimental age
Not applicable
Not applicable
Symptoms (severity)
None
None
2–3 yr old, 12 MPTP injections
over 2 yr
Severe (motor score of 17/25),5
stable akinesia and rigidity with
limited mobility, a flexed posture
of the trunk, facial hypomimia,
instability, freezing and action
tremor in the upper limbs.
14
35.4
Yes
Yes
2–3 yr old, 14 MPTP injections
over 2 yr
Moderate (motor scale of 14/25),5
stable akinesia and rigidity with a
flexed posture of the trunk and a
postural action tremor of the
upper limbs and occasionally of
the head.
14
31.2
Yes
Yes
Age at autopsy (yr)
Hemisphere volume (ml)
Severe SN cell loss
Cortical Ab deposition
8
34.6
No
No
8
32.7
No
No
SN, substantia nigra.
(Brodmann area 6) and anterior cingulate (area 24)
cortices at the anterior caudate level, precentral cortex
(area 4) dyed red before sectioning, primary visual cortex (area V1) around the calcarine sulcus, hippocampus
at the level of the lateral geniculate nucleus, amygdala,
midbrain, midpons and cerebellum, and medulla oblongata through the dorsal motor nucleus of the vagus
nerve. Tissue samples were paraffin-embedded, sectioned at 10 lm and stained with haematoxylin and eosin, modified Bielschowsky and Gallyas silver stains,
and peroxidase immunohistochemistry for tyrosine
hydroxylase (TH, sc-7847, Santa Cruz Biotechnology,
USA, diluted 1:300 following 0.2 M citrate buffer
microwave antigen retrieval), a-synuclein (sheep polyclonal raised against amino acids 116–131, a gift from
W.P. Gai, Flinders University, Australia, diluted 1:500
following 1 mM EDTA pH 8.0 microwave antigen retrieval), phosphorylated a-synuclein (mouse monoclonal P-S129, a gift from W.P. Gai, Flinders University,
Australia, diluted 1:10,000 following formic acid and
0.2 M citrate buffer microwave antigen retrieval), ubiquitin (Z0458 Dako, Denmark, diluted 1:200), phosphotau (AT8, MN1020 Pierce Endogen, Rockford, USA,
diluted 1:10,000), Ab (mouse monoclonal clone IE8, a
gift from C. Masters, University of Melbourne, Australia, diluted 1:100 following formic acid antigen retrieval), and Tar DNA binding protein 43 (TDP43,
10782-2-AP ProteinTech Group, Chicago, USA,
diluted 1:500 following 0.2 M citrate buffer microwave
antigen retrieval). Tissue samples from the hippocampus and temporal cortices and brainstem of a case with
dementia with Lewy bodies (aged 78 at death, 6 years
disease duration) and the midbrain of a human control
case (aged 85, no significant pathological abnormalities) were included as positive controls, and the specificity of the reaction tested by removal of primary antibodies resulting in no reaction product.
Movement Disorders, Vol. 24, No. 10, 2009
RESULTS
The fixed hemispheres were of similar size (Table 1)
with no external abnormalities. Examination of the cut
slices revealed discoloration of the substantia nigra and
globus pallidus in control M2 and MPTP-primates M3
and M4 (Fig. 1E) compared with control M1 (Fig. 1A),
consistent with increasing age. Histological examination revealed punctate ubiquitin-immunoreactive structures in the upper layers of the cortex and in the hippocampus and amygdala in control M2 and MPTP-primates M3 and M4 (data not shown), consistent with
previously described age-related changes observed in
humans and other species.7–9 Other pathological abnormalities were only seen in the MPTP-primates. In these
primates, there was severe loss of neurons and gliosis
in the substantia nigra pars compacta (SNc, Fig. 1C
versus 1G). The loss of the A9 dopaminergic SNc neurons was selective, as nearby and remote TH-immunoreactive neurons remained intact, including the A8 and
A10 midbrain dopaminergic neurons (Fig. 1B versus
1F), pontine noradrenergic neurons (Fig. 1J versus
1K), and the catecholaminergic neurons in the medulla
oblongata (data not shown). In the MPTP-primates,
TH-immunoreactive fibers and terminals were absent
from the basal ganglia but were present in the cortex
and amygdala (data not shown).
Selective regions contained abnormal protein accumulation only in the MPTP-primates. Increased a-synuclein and phosphorylated a-synuclein immunoreactivity was observed in the few remaining SNc neurons
with an increase in punctate structures in the neuropil
(Fig. 1D versus 1H). Similar punctate but not intraneuronal staining was observed in the SNc with ubiquitin immunohistochemistry (data not shown). The
increased intraneuronal a-synuclein immunoreactivity
was not in the structural form of Lewy bodies but
appeared as a substantial mass of particles within the
FIG. 1. Histopathological comparison of control and MPTP-treated primates. A, E: Transverse brainstem slices through the midbrain reveal discoloration of the substantia nigra in control M2 and MPTP-primates M3 and M4 (E) compared with control M1 (A). B, F: Tyrosine hydroxylase
(TH) immunoreactivity is abundant in both the substantia nigra pars compacta (arrows) and A8 dopaminergic cell group (open arrowhead) of the
controls (M1 shown in B), but there is selective loss of the A9 TH-positive neurons in the pars compacta (arrows) of the MPTP-primates, while
the A8 group is unaffected (open arrowhead, M4 shown in F). C, G: Haematoxylin and eosin staining shows severe neuronal loss and gliosis in
the substantia nigra pars compacta of the MPTP-primates (M4 shown in G) compared with the controls (M1 shown in C). D, H, I: a-Synuclein
immunoreactivity appears as diffuse and punctate in the neuropil and as granules within the cytoplasm of substantia nigra neurons in controls
(M1 shown in D). In MPTP-primates (M4 shown in H) small dense aggregates of a-synuclein immunoreactivity are observed in surviving neurons
and in the neuropil. a-Synuclein-immunoreactive Lewy bodies are present in pigmented and nonpigmented locus coeruleus neurons in Parkinson’s
disease (I). Lewy bodies are not observed in the MPTP-primates (H) or controls. J, K: Tyrosine hydroxylase (TH) immunoreactivity is not
reduced in the locus coeruleus of MPTP-primates (M3 shown in K) compared with controls (M1 shown in J).
1522
G. HALLIDAY ET AL.
neuronal cytoplasm (Fig. 1H versus 1I). No other
abnormal intraneuronal protein immunoreactivity was
observed in the brainstem using the protocols outlined.
Within the amygdala and temporal cortices, extracellular Ab aggregations were observed only in the MPTPprimates (data not shown). Phosphorylated tau immunoreactivity was not associated with these Ab plaques
(data not shown).
DISCUSSION
This study confirms that intravenous intoxication
with MPTP in primates results in Parkinsonism with
selective dopaminergic loss and a-synuclein aggregation in the SNpc.10,11 From recent studies,12 it would
appear that this aggregation is related to the death of
these neurons. We directly addressed the hypothesis
that substantial time is required post nigral insult for
the classic cellular aggregation of a-synuclein into
Lewy bodies. Despite the MPTP-primates studied having Parkinsonism for over a decade, no classic a-synuclein-immunopositive Lewy body inclusions were
observed in any of the brain regions sampled. This is
consistent with similar studies in MPTP-primates with
shorter parkinsonian durations,10–12 as well as with primate models of Parkinsonism using viral vector-mediated overexpression of a-synuclein in the ventral midbrain.13
Our conclusions need to be tempered by two confounding factors. First, the limited number of animals
studied. Second, the age reached by these monkeys,
despite being much higher than usual for MPTP
experiments, may not be sufficient to facilitate Lewy
body formation. Nevertheless, Lewy bodies have not
been encountered even in older animals treated with
MPTP (J. Kordower, personal communication). Indeed,
in all of these primate models, the severity of a-synuclein-immunostained pathology is significantly less
than that found in cases with idiopathic PD, and similar to pathology observed in patients with parkin gene
deletions (neuronal loss largely restricted to the substantia nigra).14–17 In contrast, transplanted fetal midbrain dopaminergic neurons surviving for similar timeframes in the brains of patients with PD contain classic
neuronal Lewy body inclusions, with the number of
neurons affected relating to transplant survival time.3
This suggests that the possible underlying mechanisms
for Lewy body formation are not likely to be exclusively related to increased oxidative stress, excitotoxicity, or inflammation (all occur in the MPTP-primate
model), leaving the concept of permissive templating,
as recently canvassed.3,18,19 It also suggests that two
Movement Disorders, Vol. 24, No. 10, 2009
mechanisms occur, one that initially targets nigral neuronal loss (oxidative stress, excitotoxicity, and/or
inflammation) and the other responsible for Lewy body
formation (permissive templating).
It remains unclear what then underlies the initial
protein aggregation that is templated in PD. In most
parkin deletion cases and MPTP-primate models, the
selective nigral loss underlying their Parkinsonism
occurs in teenage or early adulthood, rather than in
advanced age as observed in sporadic PD. In fact, it is
age rather than disease duration that influences the severity of Lewy body pathology in PD,4,20 and age is
considered the most important determinant of clinical
progression in PD.21 Age is a factor known to increase
a-synuclein protein in nigral neurons22 by increasing
its posttranslational stabilization rather than mRNA
expression,23 whereas MPTP increases both the posttranslational stabilization and mRNA expression of asynuclein.11,24 The greater lifespan of humans may in
fact make Lewy bodies unique to humans compared
with other primates through an aging neural environment that allows permissive templating. Further modeling of these long-term effects is necessary.
Acknowledgments: For the primate work, MT Herrero
received support from the Spanish Ministry of Science (SAF2004/07656/C02-02), Fundación Se´neca (FS/05662/PI/07),
and CIBERNED (Area 5). The histology was funded by the
Prince of Wales Medical Research Institute. Glenda Halliday
is a Principal Research Fellow of the National Health and
Medical Research Council of Australia. Other grants held
over the last year by GM Halliday are from the National
Health and Medical Research Council of Australia (projects
#400909, #401537, #510148, #510186; equipment #520950),
Australian Research Council (SPIRIT #LP0776735) and
GlaxoSmithKline Australia (Postgraduate Support Grant), by
MT Herrero are from Spanish Ministry of Science (SAF
2007-62262) and Consejerı́a de Industria CARM (BIO-MED
0701-0006), by H Mori are from the Japanese Ministry of
Health, Labor and Welfare (Intractable Diseases, Health and
Labor Sciences Research Grants), and by JA Obeso are from
the Spanish Government-Science And Education Department
(*SAF2005-08416-C02-01*) and Novartis Pharmaceutica
(Role of Homocysteine in cognitive impairment in Parkinson’s disease). K Murphy, H McCann, F Ros-Bernal, C Barcia, and FJ Blesa have no financial disclosures. We thank
Heidi Cartwright for the preparation of the figure.
Author Roles: GM Halliday: Conception and organization
of the histopathology, and writing of the first draft of the
manuscript. Statistical design not applicable.
MT Herrero: Conception, organization, and execution of
the monkey experiments and long term care, and manuscript
review and critique. Statistical design not applicable.
NO -SYNUCLEIN DEPOSITION IN MPTP MONKEYS
K Murphy: Execution of the histopathology, and
manuscript review and critique. Statistical design not applicable.
H McCann: Execution of the histopathology, and manuscript review and critique. Statistical design not applicable.
F Ros-Bernal: Execution of the monkey experiments and
long term care, and manuscript review and critique. Statistical design not applicable.
C Barcia: Execution of the monkey experiments and long
term care, and manuscript review and critique. Statistical
design not applicable.
H Mori: Conception of parkin comparison, and manuscript
review and critique. Statistical design not applicable.
FJ Blesa: Execution of the monkey experiments, and
manuscript review and critique. Statistical design not applicable.
JA Obeso: Conception and organization of the entire project, and manuscript review and critique. Statistical design
not applicable.
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3. Brundin P, Li JY, Holton JL, Lindvall O, Revesz T. Research in
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5. Herrero MT, Hirsch EC, Kastner A, et al. Does neuromelanin
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6. Barcia C, Sanchez Bahillo A, Fernandez-Villalba E, et al. Evidence of active microglia in substantia nigra pars compacta of
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7. Borras D, Ferrer I, Pumarola M. Age-related changes in the brain
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9. Iseki E, Odawara T, Li F, et al. Age-related ubiquitin-positive
granular structures in non-demented subjects and neurodegenerative disorders. J Neurol Sci 1996;142:25–29.
10. Kowall NW, Hantraye P, Brouillet E, Beal MF, McKee AC, Ferrante RJ. MPTP induces a-synuclein aggregation in the substantia nigra of baboons. Neuroreport 2000;11:211–213.
11. Purisai MG, McCormack AL, Langston WJ, Johnston LC, Di
Monte DA. a-Synuclein expression in the substantia nigra of
MPTP-lesioned non-human primates. Neurobiol Dis 2005;20:
898–906.
12. McCormack AL, Mak SK, Shenasa M, Langston WJ, Forno LS,
Di Monte DA. Pathologic modifications of a-synuclein in 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated squirrel monkeys. J Neuropathol Exp Neurol 2008;67:793–802.
13. Eslamboli A, Romero-Ramos M, Burger C, et al. Long-term consequences of human a-synuclein overexpression in the primate
ventral midbrain. Brain 2007;130:799–815.
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14. Hayashi S, Wakabayashi K, Ishikawa A, et al. An autopsy case
of autosomal-recessive juvenile Parkinsonism with a homozygous
exon 4 deletion in the parkin gene. Mov Disord 2000;15:884–
888.
15. Sasaki S, Shirata A, Yamane K, Iwata M. Parkin-positive autosomal recessive juvenile Parkinsonism with a-synuclein-positive
inclusions. Neurology 2004;63:678–682.
16. Gouider-Khouja N, Larnaout A, Amouri R, et al. Autosomal recessive Parkinsonism linked to parkin gene in a Tunisian family.
Clinical, genetic and pathological study. Parkinsonism Relat Disord 2003;9:247–251.
17. Mori H, Kondo T, Yokochi M, et al. Pathologic and biochemical
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18. Braak H, Del Tredici K. Invited Article: nervous system pathology in sporadic Parkinson disease. Neurology 2008;70:1916–
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Movement Disorders, Vol. 24, No. 10, 2009
1524
I. KRAOUA ET AL.
Parkinsonism in Gaucher’s
Disease Type 1: Ten New Cases
and a Review of the Literature
Ichraf Kraoua, MD,1 Jérôme Stirnemann, MD,2
Maria João Ribeiro, MD, PhD,3 Tiphaine Rouaud, MD,4
Marc Verin, MD, PhD,4 Agnès Annic, MD,5
Christian Rose, MD, PhD,6 Luc Defebvre, MD, PhD,5
Liliane Réménieras, MD,7 Michaël Schüpbach, MD,1
Nadia Belmatoug, MD,8 Marie Vidailhet, MD,1,9
and Frédéric Sedel, MD, PhD1*
1
Federation of Nervous System Diseases, Reference
Center for Lysosomal Diseases, Salpeˆtrie`re Hospital,
Assistance Publique-Hôpitaux de Paris, France;
2
Department of Internal Medicine, Jean Verdier Hospital,
Assistance Publique-Hôpitaux de Paris,
Paris X111 University, France; 3Service Hospitalier
Fre´de´ric Joliot, I2BM, DSV,
CEA, Orsay, France; 4Department of Neurology,
University Hospital of Rennes, Rennes, France;
5
Department of Neurology, University Hospital of Lille,
Lille, France; 6Department of Onco-Haematology,
Saint Vincent de Paul Hospital, Lille, France;
7
Department of Haematology, University Hospitals
of Limoges, Limoges, France; 8Department of Internal
Medicine, Reference Center
for Lysosomal Diseases, Beaujon Hospital,
Assistance Publique-Hôpitaux de Paris, France; 9INSERM
U679, Pierre et Marie Curie (Paris 6)
University, France
Abstract: Parkinsonism has been described in patients
with Gaucher’s disease (GD). We reviewed the 10 cases of
patients with both parkinsonism and GD recorded in the
French national GD registry, as well as 49 previously
published cases. Relative to the general population, parkinsonism in GD patients (1) was more frequent, (2)
occurred at an earlier age, (3) responded less well to levodopa, and (4) was more frequently associated with signs
of cortical dysfunction. Enzyme replacement therapy
(ERT) and substrate reduction therapy (SRT) were ineffective on GD-associated parkinsonism, suggesting that
parkinsonism itself is not an indication for ERT or SRT
in this setting. Ó 2009 Movement Disorder Society
Key words: Gaucher; glucocerebrosidase; parkinsonism;
Parkinson’s disease; Lewy body dementia
*Correspondence to: Dr. Frédéric Sedel, Federation of Nervous
System Diseases and Reference Centre for Lysosomal Diseases, Salpêtrière Hospital, 47 Boulevard de l’Hôpital, 75651 Paris cedex 13,
France. E-mail: frederic.sedel@psl.aphp.fr
Potential conflict of interest: None reported.
Received 9 February 2009; Accepted 17 March 2009
Published online 9 June 2009 in Wiley InterScience (www.
interscience.wiley.com). DOI: 10.1002/mds.22593
Movement Disorders, Vol. 24, No. 10, 2009
Gaucher’s disease (GD) is the most frequent inherited lysosomal storage disorder.1 It is due to autosomal
recessive inherited glucocerebrosidase (GBA) deficiency resulting in glucocerebroside accumulation,
mainly in macrophage lysosomes. Enzyme replacement
therapy (ERT) is the treatment of choice, whereas
miglustat, a small sugar molecule, can be used to inhibit glucocerebroside synthesis and accumulation.1
GD is classified into three variants, based on age at
onset, the disease course, and the presence or absence
of neurological signs.1,2 Type 1 (non-neuronopathic)
GD accounts for around 95% of cases. Clinical manifestations can appear at any age and usually include
hepatosplenomegaly, thrombocytopenia, and bone involvement. The course is chronic and the nervous system is, by definition, respected.
This classification of GD into neuronopathic forms
(types 2 and 3) and a non-neuronopathic form (type 1)
has been challenged by recent studies showing heterogeneous neurological disorders in patients with GD
type 1.3–5 An association between GD and parkinsonism was initially described in case reports6–11 and then
in a series of six patients described by Neudorfer
et al.12 Thirty-seven well-characterized cases has since
been published.13–25 It is difficult, however, to obtain
an accurate clinical picture from these reports. In addition, recent studies have demonstrated that heterozygous mutations in the GBA gene contribute to vulnerability to parkinsonism.26–28
The aim of this study was to obtain a more precise
picture of GD-associated parkinsonism (PD/GD), based
on a retrospective analysis of 10 cases contained in the
French national GD registry and on a review of the 49
previously published cases.
PATIENTS AND METHODS
From January 2002 to September 2008, 485 patients
with GD were enrolled in the French national GD
registry. In France, the diagnosis of GD is based on
measurement of enzyme activity, and only a subset of
patients are genotyped. Although neurological data are
not systematically collected in the French GD registry,
parkinsonism was mentioned in 11 patients and was
confirmed by neurologists in every case (Table 1). The
clinical data were sufficiently informative in 10 cases,
which are analyzed here. Genotyping was available for
4 of these 10 patients. Six patients were managed at
Salpêtrière Hospital in Paris, and their neurological
examinations and chart review were performed by one
of us (F.S.). Data on the remaining four patients were
obtained from the referring clinicians.
PARKINSONISM IN GAUCHER’S DISEASE TYPE 1
Positron emission tomography (PET) was performed
in two cases (#1 and #2), twice on the same day, using
two different radiotracers: 18F-fluoro-levodopa to evaluate presynaptic dopa decarboxylase activity, and 11Craclopride to estimate postsynaptic D2 dopamine receptor density. The 18F-fluoro-L-dopa uptake constant and
11
C-raclopride binding potential were compared with
mean normal control values (Table 3).
The literature was scanned via the NIH Pubmed
database with the key words ‘‘parkinsonism,’’ ‘‘Parkinson,’’ ‘‘Gaucher,’’ and ‘‘glucocerebrosidase,’’ and
using the authors’ own bibliography. Cases published
more than once were excluded by careful perusal of
publications and personal communications. Seven cases
were excluded because of insufficient data. Finally, 49
cases of GD/PD were selected from 22 articles.
RESULTS AND DISCUSSION
The characteristics of the 10 French patients are
summarized in Table 1, and those of the 49 published
cases in Table 2. Parkinsonism was recorded in 11
(2%) of the 485 patients in the French GD registry. As
neurological disorders are not systematically recorded
in this registry, the real frequency of parkinsonism in
GD patients is probably higher. In two published
cohorts of patients with GD type 1, PD was noted in
6.9%19 and 1.33% of cases.4 Overall, although comparisons should be corrected for age in larger cross-sectional studies, the prevalence of PD in GD patients
seems to be higher than the prevalence of IPD, which
is generally estimated at 0.3% in the entire population
and 1% over 60 years of age.29
The N370S mutation, which is usually considered to
be ‘‘neuroprotective,’’ was the most common mutation
both in the literature (27/35) and in our series (4/4),
followed by the L444P mutation (8/25 and 2/4 patients,
respectively).
By pooling our data with those taken from the literature, median age at onset of PD in patients with GD
was 49 years, compared with 60 to 71 years for IPD,
depending on the study.30 This comparison must be
interpreted with care, however, given the relatively
small numbers of cases and the different populations.
PD/GD patients share certain features with IPD
patients, such as asymmetric onset, akinesia, and rigidity. Resting tremor was noted in 69% of cases in the
literature and 60% of our patients (6/10), and a similar
prevalence is found in IPD.
Dementia was observed in 6 of our 10 patients and
in 38.7% of published cases. Too little information
1525
was available in most cases to characterize the precise
cognitive deficit. All our six patients had signs of executive dysfunction. In addition, we noted motor and
visuoconstructive apraxia reminiscent of cortical dysfunction in patient #2, #3, and #4. All these three
patients had visual hallucinations, leading to diagnosis
of Lewy body dementia (LBD). Interestingly, heterozygotes for GBA mutations also have a higher risk of
developing LBD.31 Here again, these apparent differences between PD/GD and IPD should not be overstated,
given the small number of GD patients with detailed
neuropsychological studies. Furthermore, the prevalence of dementia in IPD is about 30% at diagnosis
and 60% after 12 years.32
Other neurological disorders occasionally reported in
PD/GD include supranuclear gaze palsy, myoclonus,
deafness, seizures, ataxia, pyramidal signs, polyneuropathy, and dysautonomia (Table 2). None of these were
observed in our patients.
Brain MRI, when performed, was reported to be normal. In our patient #1 and #2, 18F-fluoro-L-dopa uptake
was decreased bilaterally and asymmetrically in the
caudate and putamen (see Table 3 and Fig. 1). In contrast, 11C-raclopride binding in the caudate and putamen nuclei was normal in both patients (Table 3 and
Fig. 1). These findings, together with those in another
published case,24 are highly reminiscent of IPD, which
features decreased uptake of 18F-fluoro-L-dopa consistent with asymmetric dopaminergic denervation, together with near-normal 11C-raclopride binding indicative of postsynaptic interneuron integrity.
Sustained responses to L-dopa, defined as a subjective improvement of >50% lasting >5 years, occurred
in five of eight of our patients but in only 22% of
cases reported in the literature. This suggests that
L-dopa responsiveness is much lower than in IPD.
However, many published reports did not mention the
response to L-dopa, and the term ‘‘sustained response’’
was not always clearly defined. Dyskinesias were noted
in 5 of our 10 patients and in eight published cases,
but the relevant data were unavailable for the other
patients.
Parkinsonism progressed in all GD patients who
received ERT. This is not surprising, as exogenous
enzymes are readily excluded from the CNS by the
blood-brain barrier. Miglustat, which crosses the
blood-brain barrier, has been reported to halt the progression of parkinsonism in a patient with GD.22 However, two of our patients were treated with miglustat
300 mg/day, and both stopped receiving this treatment
after 1 year because of progression of parkinsonism
(patient #1) or dementia (patient #2).
Movement Disorders, Vol. 24, No. 10, 2009
1526
Movement Disorders, Vol. 24, No. 10, 2009
TABLE 1. Summary of clinical, enzymatic, and genetic data in 10 French patients with GD and parkinsonism
Case
Age at
Age at
last Age at
onset of
follow onset
of GD Parkinsonism
up
Genotype
M
NA
41
15
38
2
M
N370S/N370S
61
60
57
3
M
N370S/L444P
65
NA
62
4
M
NA
72
47
63
5
M
NA
69
48
52
6
M
NA
60
30
45
7
F
N370S/L444P
72
NA
51
8
F
N370/RecNciI
79
4
60
9
F
NA
74
63
72
10
F
NA
64
55
61
67b
47.5b
58.5b
Total M:F 5 1.5
a
HSMG, T,
O, Pm
ST
Manifestations of
Parkinsonism
Asymmetric onset,
rigidity, akinesia,
discrete tremor
HSMG, T
2 Asymmetric onset,
rigidity, akinesia
T, HSMG,O
2 Asymetric onset,
rigidity, akinesia
HSMG, T
2 Asymmetric onset,
rigidity, akinesia,
resting tremor,
postural instability,
falls
T
1 Asymmetric onset,
rigidity, akinesia,
resting tremor,
postural instability
HSMG, O
2 Asymmetric onset,
rigidity, akinesia,
axial signs
1 Asymmetric onset,
Nonea
rigidity, akinesia,
resting tremor
HSMG, T, O
1 Asymmetric onset,
rigidity, akinesia
resting tremor,
postural instability,
falls
SMG, T, O
2 Asymmetric onset,
rigidity, akinesia
HSMG, T, O
2 Asymmetric onset,
rigidity, akinesia,
resting tremor
T: 8/10, HSMG: 4/10 Asymmetric onset
7/10, O: 6/10
10/10, rigidity,
akinesia 10/10,
tremor 6/10
1
TT
Effect of
ERT on
parkinsonism
2
1
1 (40)
2
E/M/DBS
–
1 (60)
2
1 (60)
1
M
NT
1 (64)
NA
2
2
E
–
1 (63)
2
2
NT
E
–
2
1
1 (58)
1
DBS
NT
1
1
1 (51)
1
E
NA
1 (66)
1
1 (60)
1
DBS
NT
1 (71)
NA
2
NA
E
NA
2
1
NA
NA
E
–
NA
2
NA
NA
E
–
6/9
5/8
5/8
4/6
Dementia Dopa Dyskinesia Fluctuations
(age at
(age at efficacy (age at
onset)
onset)
>5 yr
onset)
Diagnosis was made after GD was diagnosed in his sister.
Median values.
ERT, enzyme replacement therapy; E, enzyme replacement therapy, F, female; GD, Gaucher’s disease; HSMG, hepatosplenomegaly; M, male; NA, not available; NT, not treated; O, osseous involvement; SMG, splenomegaly; DBS, deep brain stimulation; ST, splenectomy; T, thrombopenia; TT, treatment; M, miglustat.
b
I. KRAOUA ET AL.
Gender
1
Manifestations
of GD
TABLE 2. Parkinsonism and Gaucher’s disease type 1: previously published cases
Sex
Mean
values
M/F
5 1.6
Age at Median age
diagnosis at onset of
of GD Parkinsonism
(yr)
(yr)
35
48
GD signs
(%)
S 5 70.8,
Hem 5 69,
H 5 64.5,
O 5 37.5
H, O
Hem
H, Hem, O
Hem
H, Hem, O
Cognitive
Splenectomy Asymetric Tremor Akinesia Rigidity decline
(%)
PD (%)
(%)
(%)
(%)
(%)
Additional
neurological
syndromes*
(%)
56.5
80.9
69.2
86.8
100
38.7
28.5
1
2
1
2
1
1
1
2
2
1
1
1
2
1
1
2
2
1
2
2
NA
NA
NA
NA
NA
1
2
2
1
2
Response to
levodopa (%)
Good 5 22.6,
poor 5 25.8,
transient 5 16,
none 5 35.5
NA
NA
NA
NA
NA
Positive
effect of
ERT on
ERT parkinsonism Surgery
(%)
(%)
(%)
Genotype
Reference
68
0
16.7
1
2
1
2
1
2
NA
2
NA
2
2
2
2
2
2
N370S/c.84dupG
N370S/N370S
N370S/Rec
N370S/N370S
N370S/L444P
25
25
25
25
25
NA
NA
NA
2
1
1
NA
2
2
2
2
2
N370S/N370S
N370S/N370S
N370S 1
IVS4-2A > G;
(2203) A > G
N370S 1
IVS4-2A > G;
(2203) A > G
L444P/D409H
L444P/L444P
L444P/L444P
25
25
5
1
2
3
4
5
M
M
F
M
F
12
61
24
38
17
44
65
51
50
56
6
7
8
M
M
F
47
26
49
50
39
NA
H, S, O
H, O
S,O
2
1
1
2
1
NA
2
1
NA
1
1
NA
NA
NA
NA
2
2
1
Myoclonus
NA
NA
NA
Complex
seizures
NA
NA
2
9
F
60
NA
O
2
NA
NA
NA
NA
NA
2
NA
2
2
2
10
11
12
M
M
M
10
41
49
NA
49
NA
S, O
H, S, Hem
H, S, Hem
1
1
1
NA
NA
NA
NA
1
NA
NA
1
1
NA
1
1
NA
1
1
NA
Good
NA
1
2
2
2
2
2
2
2
13
14
15
16
17
18
19
20
21
22
23
M
M
M
M
F
F
F
M
M
M
F
6
67
22
22
23
53
64
30
62
30
9
33
74
43
44
43
59
55
40
63
45
47
H, S, O
H, S, Hem
H, S, Hem, O
H, S, Hem
H, S, Hem
H, S, Hem
S, Hem
S, O, Hem
H, S, Hem
S, Hem
H
1
2
1
2
1
1
2
2
1
1
1
1
NA
1
1
1
1
1
NA
2
NA
NA
2
1
1
1
1
1
1
1
1
1
2
1
NA
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
NA
NA
NA
NA
2
2
2
2
SGP
SGP deafness
Neck dystonia,
chorea, SGP,
pyramidal sd
SGP
Good
None
Poor
Transient
Transient
Good
Good
None
None
Poor
Poor
1
1
1
1
1
1
2
1
1
1
NA
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
1
2
2
2
2
2
2
L444P/F213I
N370S/N370S
N370S/L444P
N370S/L444P
G377S/G377S
N370S/?
N370S/?
R463C/R120W
N370S/V394L
N370S/c.1263–1317
N370S/N370S
24
22
21
19
19
19
19
18
18
18
18
24
M
46
49
H, S, Hem, O
2
NA
1
1
1
1
None
1
2
2
G377S/G377S
20
25
F
23
43
H, S, Hem
1
1
1
NA
1
NA
Transient
1
2
1
G377S/G377S
17
Deafness
Deafness
2
2
Bulbar signs
Ataxia
2
Psy, saccades
abnormalities
Myoclonus,
SGP
2
5
5
23
23
TABLE 2. (Continued)
Age at
Median age
diagnosis at onset of
of GD Parkinsonism
Sex
(yr)
(yr)
GD signs
(%)
Splenectomy Asymetric Tremor Akinesia Rigidity
(%)
PD (%)
(%)
(%)
(%)
Cognitive
decline
(%)
26
27
28
29
30
31
32
33
34
M
M
M
M
F
M
F
M
F
28
60
NA
53
40
44
48
NA
19
48
62
47
59
50
60
45
40
42
H, S, O
H, S, Hem
2
H, Hem
H
H, S, O
2
S
H, S, Hem
NA
NA
2
1
1
2
2
2
1
NA
NA
NA
NA
1
1
NA
NA
1
1
1
NA
1
1
NA
NA
2
1
NA
1
NA
NA
NA
1
1
1
1
1
NA
NA
1
1
1
1
1
1
1
NA
NA
NA
1
1
NA
1
2
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
M
M
F
M
M
M
F
F
F
F
M
M
F
F
M
40
27
NA
5
32
32
32
32
32
17
25
56
NA
29
40
50
39
NA
33
48.8
48.8
48.8
48.8
48.8
48
38
46
55
43
39
NA
S, Hem
S,O
H, S, Hem
H, S, Hem
H, S, Hem
H, S, Hem
H, S, Hem
H, S, Hem
H, S, Hem, O
S, Hem
O, Hem
O, Hem
H, S, Hem
S, Hem
NA
2
1
1
1
1
2
2
2
1
1
2
2
1
2
NA
NA
NA
NA
NA
NA
NA
NA
NA
1
NA
1
NA
1
NA
NA
2
NA
1
1
1
2
2
2
2
1
2
NA
1
2
NA
1
NA
1
1
1
1
1
1
1
1
1
1
1
2
NA
1
NA
1
1
1
1
1
1
1
1
1
1
1
1
1
2
NA
NA
NA
NA
NA
NA
NA
2
2
2
1
2
2
Additional
neurological
syndromes*
(%)
2
2
2
2
2
2
2
2
SGP,
myoclonus
2
2
NA
2
2
2
2
2
Myoclonus
2
2
2
SGP
2
2
Positive
effect of
ERT on
Response to ERT parkinsonism Surgery
levodopa (%) (%)
(%)
(%)
Reference
Genotype
NA
Poor
NA
Poor
Poor
Poor
Transient
Poor
None
NA
1
NA
1
NA
1
2
1
1
NA
2
NA
NA
NA
NA
NA
NA
2
2
2
NA
2
2
2
2
1
1
N370S/c.84–85 insG
N370S/N370S
N370S/c.500 ins T
N370S/?
N370S/?
N370S/N370S
N370S/N370S
N370S/N370S
L444P/D409H
17
17
17
17
17
17
17
17
16
NA
None
NA
None
None
None
None
Good
Good
Transient
None
Good
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
1
2
NA
NA
2
2
NA
NA
NA
NA
NA
NA
NA
NA
NA
2
NA
NA
NA
NA
NA
2
2
2
1
1
2
2
2
2
2
1
2
2
2
2
NA
N370S/IVS2 1 1
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
15
14
13
12
12
12
12
12
12
10
11
9
8
7
6
Nonavailable data (NA) were excluded from mean calculations.
*Includes SGP, 16.3% myoclonus, 9.3% deafness, 6.9% epilepsy (1 case), ataxia (1 case), bulbar signs (1 case).
A, anemia; F, female; H, hepatomegaly; Hem, hematologic signs (include anemia, thrombopenia, or leucopenia); M, male; O, osseous involvement; Psy, psychiatric disorders; S, splenomegaly; SGP, supranuclear
gaze palsy;, 2, no; 1, yes.
PARKINSONISM IN GAUCHER’S DISEASE TYPE 1
1529
TABLE 3. Uptake values in controls and patients 1 and 2 obtained for each radiotracer
Right caudate
Left caudate
Right putamen
Left putamen
0.0123 6 0.0014
0.0055
0.0088
0.0123 6 0.0013
0.0035
0.0077
0.0118 6 0.0009
0.0033
0.0056
0.0116 6 0.0014
0.0030
0.0049
2.75 6 0.24
3.02
2.13
2.75 6 026
3.08
2.05
2.98 6 0.16
3.70
2.87
3.03 6 0.25
4.20
2.73
18
Uptake constant, F-fluoro-L-dopa
Controls (mean 6 SD)
Patient 1
Patient 2
Binding potential, 11C-raclopride
Controls (mean 6 SD)
Patient 1
Patient 2
Author Roles: Research project: Conception: Frédéric
Sedel, Jerome Stirnemann, Nadia Belmatoug, Marie Vidailhet; Organization: Frédéric Sedel, Ichraf Kraoua, Nadia Belmatoug, Jerome Stirnemann; Execution: Ichraf Kraoua,
Tiphaine Rouaud, Marc Verin, Agnès Annic, Christian Rose,
Luc Defebvre, Liliane Réménieras, Michaël Schüpbach; PET
studies: Maria-Joao Ribeiro. Statistical analysis: Design and
execution: Frederic Sedel, Ichraf Kraoua, Marie Vidailhet;
Manuscript: Writing of the first draft: Ichraf Kraoua; Review
and critique: Frédéric Sedel, Jerome Stirnemann, Nadia Belmatoug, Marie Vidailhet, Tiphaine Rouaud, Marc Verin,
Agnès Annic, Christian Rose, Luc Defebvre, Liliane Réménieras, Michaël Schüpbach, Maria-Joao Ribeiro.
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FIG. 1. Fusion of MRI and 18F-fluoro-L-dopa images (A), and 11Craclopride (B) in a control (1) and in patient #1 (2). [Color figure
can be viewed in the online issue, which is available at www.
interscience.wiley.com.]
In conclusion, although this study is limited by its
retrospective nature, PD/GD seems to differ from IPD
in the following respects: (1) younger age at onset, (2)
a poorer or transient response to L-dopa, (3) and a
higher incidence of cognitive dysfunction reminiscent
of LBD. In contrast, PD/GD shares with IPD its asymmetric onset, akinesia, rigidity, resting tremor and, in
some cases, dopa-induced dyskinesias. Although GD
may be a risk factor for PD, the vast majority of
patients with GD type 1 will never develop neurological problems. Although further prospective studies are
needed, parkinsonism should not itself be considered
an indication for ERT or SRT.
Acknowledgment: Dr. Kraoua has received funding from
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Movement Disorders, Vol. 24, No. 10, 2009
Bell’s Palsy Preceding Parkinson’s
Disease: A Case-Control Study
Rodolfo Savica, MD,1,2 James H. Bower, MD, MSc,2
Demetrius M. Maraganore, MD,2
Brandon R. Grossardt, MS,3
and Walter A. Rocca, MD, MPH1,2*
1
Division of Epidemiology, Department of Health Sciences
Research, College of Medicine, Mayo Clinic, Rochester,
Minnesota, USA; 2Department of Neurology, College of
Medicine, Mayo Clinic, Rochester, Minnesota, USA;
3
Division of Biomedical Statistics and Informatics,
Department of Health Sciences Research, College of
Medicine, Mayo Clinic, Rochester, Minnesota, USA
Abstract: We investigated the association of Bell’s palsy
(BP) with the subsequent risk of Parkinson’s disease (PD)
using a case-control study design. We matched 196 incident cases of PD in Olmsted County, MN, to 196 general
population controls with same age (61 year) and sex, and
we reviewed the complete medical records of cases and
controls in a medical records-linkage system to detect BP.
Six of the 196 patients with PD and none of the 196 controls were diagnosed with BP before PD (exact binomial
probability, P 5 0.02). The median age at occurrence of
BP was 49.5 years (range, 15–84 years) and the median
time between BP and the onset of PD was 27.5 years
(range, 2–54 years). The findings were similar using a
standardized incidence ratio (SIR) approach, but were
not statistically significant. This initial association between
BP and PD awaits replication. Ó 2009 Movement Disorder
Society
Key words: Bell’s palsy; Parkinson’s disease; case-control
study; risk factors
A recent study of a three-generation Mexican family
showed the occurrence of both Parkinson’s disease
(PD) and Bell’s palsy (BP) in 2 of 21 members. In
addition, 1 family member had both BP and essential
tremor (ET), and 5 additional members had isolated
BP.1 Prompted by this report, and by the observation
Dr. Savica conducted the study while on leave from the Department of Neurosciences, Psychiatry, and Anesthesiology, University
of Messina, Italy.
*Correspondence to: Dr. Walter A. Rocca, Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, 200
First Street SW, Rochester, MN 55905. E-mail: rocca@mayo.edu
Potential conflict of interest: None reported.
Received 17 November 2008; Revised 25 February 2009;
Accepted 24 March 2009
Published online 15 June 2009 in Wiley InterScience (www.
interscience.wiley.com). DOI: 10.1002/mds.22616
BELL’S PALSY AND PARKINSON’S DISEASE
of some PD patients with preceding BP in our clinical
series, we formally tested the association between BP
and PD in a case-control study conducted in Olmsted
County, MN.2-4
METHODS
Cases and Controls
We used the medical records-linkage system of the
Rochester Epidemiology Project to identify all subjects
residing in Olmsted County who developed PD from
1976 through 1995. Details about the study population
and the identification of incident cases were reported
elsewhere.5 Our diagnostic criteria included two steps:
the definition of parkinsonism as a syndrome and the
definition of PD within the syndrome. Parkinsonism
was defined as the presence of at least two of four
cardinal signs: rest tremor, bradykinesia, rigidity, and
impaired postural reflexes. PD was defined as the presence of parkinsonism with all three of the following
criteria: (1) No other cause (e.g., repeated stroke with
step-wise progression; repeated head injury; history of
encephalitis; neuroleptic treatment within 6 months
before onset; hydrocephalus; brain tumor). (2) No documentation of unresponsiveness to levodopa at doses
of at least 1 g/day in combination with carbidopa
(applicable only to patients who were treated). (3) No
prominent or early (within 1 year of onset) signs of
more extensive nervous system involvement (e.g., dementia or dysautonomia) not explained otherwise.5 Our
clinical classification of patients with PD through medical record review was found to be valid compared
with a direct examination by a movement disorders
specialist, as reported elsewhere.6 Onset of PD was
defined as the year in which a cardinal sign of PD was
first noted by the patient, by family members, or by a
care provider (as recorded in the medical record).
Each case was individually matched by age (61
year) and sex to a general population control residing
in Olmsted County and free of PD, other parkinsonism,
or tremor of any type in the index year (year of onset
of PD in the matched case). The list of all county residents from which potential controls were randomly
drawn was provided by the medical records-linkage
system.7 Records of potential controls were reviewed
by a neurologist (D.M.M.) to exclude the presence of
PD, other types of parkinsonism, or tremor of any type
before or during the index year. The presence of dementia or other neurologic diseases was not an exclusion criterion. Our exclusion of parkinsonism in controls through medical record review was found to be
valid compared with a direct examination by a move-
1531
ment disorders specialist, as reported elsewhere.6 Further details about the identification of controls were
reported elsewhere.6
Ascertainment of Bell’s Palsy
The complete medical records of cases and controls
archived by the medical records-linkage system were
reviewed by a neurologist (R.S.) who abstracted all information related to possible BP (e.g., age at onset, duration
of symptoms, and side of the palsy). The neurologist
abstracted only symptoms or diagnoses that occurred
before the onset of PD or the index date. To avoid a possible bias in the abstraction of data,8 we only included subjects who were given a diagnosis of BP by their caregiving
physicians (historically, at the time of medical evaluation).
In addition, we conducted an independent search for
all the International Classification of Diseases codes
related to facial palsies using the electronic diagnostic
index of the Rochester Epidemiology Project (International Classification of Diseases, Adapted Code for
Hospitals—H-ICDA).9 We searched for 34 codes in
the 03500 block plus the code 05312. Of the 392 cases
or controls, 11 subjects were found to have at least one
code of interest. However, one case had a facial palsy
following a surgery, one case had a congenital facial
palsy, and one case had no details about the palsy
within the medical record. Similarly, two controls had
facial palsy following surgery. These 3 cases and 2
controls were considered free of BP. The remaining 6
patients with BP preceding PD were the same as those
identified via active records review by the neurologist
(R.S.).
Data Analysis
We used the exact binomial probability to estimate a
P value for the difference in frequency of BP between
cases and controls. The odds ratio was not estimable
because none of the controls were exposed. To confirm
our findings, we also compared the number of BP
events observed among cases with the number of BP
events expected using the age- and sex-specific incidence rates from the overall Olmsted County population.10 This method also allowed us to explore the
association in men and women separately.
RESULTS
We identified 202 incident patients with PD from
1976 through 1995, and these patients were matched by
age and sex with 202 controls. However, 6 individuals
(5 cases and 1 control) did not authorize the use of their
medical records for research and the corresponding pairs
Movement Disorders, Vol. 24, No. 10, 2009
1532
R. SAVICA ET AL.
TABLE 1. Clinical characteristics of the six patients with Bell’s palsy preceding Parkinson’s disease
Patient
number
1
2
3
4
5
6
Sex*
Age at
onset of
BP
Side
affected
by BP
Duration
of BP
Age at
onset
of PD
Years
from BP
to PD
Laterality
of PD
Initial
symptom
of PD
Type
of PD
L-dopa
response
W
W
M
W
M
W
84
15
61
58
41
34
L
R
L
L
L
R
1 month
2 months
1 month
1 month
20 days
unknown
86
69
91
73
72
59
2
54
30
15
30
25
L
R
L
L
R
R
IG
IG
Rigidity
Tremor
Tremor
Tremor
AR
AR
Tremora
Tremora
Tremora
Tremora
Yes
Yes
Not takenb
Yes
Yes
Yes
*The overall sample of patients with PD (cases) included 121 (61.7%) men and 75 (38.3%) women.
a
Tremor-predominant form of PD.
b
Patient number 3 did not receive L-dopa because the symptoms of PD were mild and progressed slowly.
BP, Bell’s palsy; PD, Parkinson’s disease; W, woman; M, man; R, right; L, left; IG, impaired gait; AR, akinetic-rigid.
could not be studied. Therefore, we included 196 casecontrol pairs for a total of 392 individuals. Among the
cases, 121 (61.7%) were men and 75 (38.3%) were
women; the median age at onset of PD was 71 years
(range, 41–97 years). The distribution by age and sex
was similar in controls because of the matched design.
Six of the 196 patients with PD and none of the 196
controls had BP before the index-year. The difference
in frequency was statistically significant (P 5 0.02).
Table 1 summarizes the clinical features of the 6 subjects with BP. The median age at onset of BP was
49.5 years (range, 15–84 years) and the median age at
onset of PD was 72.5 years (range, 59–91 years). The
median time between the occurrence of BP and PD
was 27.5 years (range, 2–54 years). All subjects were
L-dopa responsive, except one who did not receive Ldopa because the symptoms were mild and progressed
slowly. None of the 6 patients was affected by diabetes
mellitus. Using incidence rates of BP from Olmsted
County, we expected 2.72 BP events among the 196
cases, yielding an overall standardized incidence ratio
(SIR) of 2.21 (95% CI 5 0.81 to 4.80; P 5 0.12). The
SIR was 1.29 in men (95% CI 5 0.16 to 4.65; P 5 0.92)
and 3.41 in women (95% CI 5 0.93 to 8.74; P 5 0.06).
DISCUSSION
In this population-based case-control study, we
found a previously unrecognized association between
BP and PD. There is a previous description of the concurrent presence of BP, ET, and PD in a Mexican family. In particular, both BP and PD were present in the
same individual in 2 of the 21 family members (over
three generations).1 However, we are not aware of any
additional studies that reported this association.
The association observed in our study may be due to
chance (Type 1 error) and needs to be replicated. If the
finding is replicated, it may have three possible explana-
Movement Disorders, Vol. 24, No. 10, 2009
tions. First, some unknown genetic factors may be associated with both BP and PD. This hypothesis is consistent
with the aggregation of BP and PD in one family.1 However, there is no other supporting evidence. Second, the
development of BP prior to PD could be a manifestation
of the early degeneration of the peripheral nervous system
that precedes the motor onset of PD.11 The fairly long median time between BP and the diagnosis of PD (27.5
years) may support this hypothesis. However, there are no
previous descriptions of facial nerve involvement in the
parkinsonian degenerative process, and BP does not correlate with any specific neuropathological findings. Third,
BP could represent an early inflammatory reaction against
antigens in the nervous system that later leads to PD. In
support of this hypothesis, both BP and PD have been
associated with inflammatory mechanisms.4,12–14
Our case-control study has several strengths. First, it
was based on a series of incident PD cases and on
well-defined general population controls, thus avoiding
referral bias and prevalence-incidence bias.8 Second,
we were able to detect BP before the occurrence of PD
using medical records information, thus avoiding recall
bias.8 Third, the ascertainment of BP was confirmed
by using electronic diagnostic codes, thus excluding a
possible bias in data abstraction.8
Our study also has a number of limitations. First,
there is limited prior evidence in support of this association; thus, the finding could be due to chance. Second,
the small number of subjects with BP in our study limited the statistical power. Third, some subjects who
suffered from mild BP may have remained unrecognized and undiagnosed; thus, they were not documented in the medical records-linkage system. This
underascertainment should be uncommon and similar
for cases and controls. In summary, we report an association between BP and PD, and we expect that this
initial finding will prompt further epidemiologic or laboratory studies.
VERTICAL OKN IN PARKINSON’S DISEASE
Acknowledgments: This work was supported by the NIH
grants R01 NS033978 and R01 AR030582. The authors have
no substantial direct or indirect commercial financial incentive associated with publishing the article.
Author roles: (1) Research project: A. Conception
(Savica, Rocca), B. Organization (Savica, Rocca), C. Execution (Savica, Rocca); (2) Statistical Analysis: A. Design
(Savica, Grossardt, Rocca), B. Execution (Grossardt, Savica),
C. Review and Critique (Grossardt, Savica, Rocca); (3)
Manuscript: A. Writing of the first draft (Savica), B. Review
and Critique (Bower, Maraganore, Grossardt, Rocca).
REFERENCES
1. Deng H, Le WD, Hunter CB, Mejia N, Xie WJ, Jankovic J. A
family with Parkinson disease, essential tremor, bell palsy, and
parkin mutations. Arch Neurol 2007;64:421–424.
2. Frigerio R, Elbaz A, Sanft KR, et al. Education and occupations
preceding Parkinson disease: a population-based case-control
study. Neurology 2005;65:1575–1583.
3. Bower JH, Maraganore DM, Peterson BJ, McDonnell SK, Ahlskog JE, Rocca WA. Head trauma preceding PD: a case-control
study. Neurology 2003;60:1610–1615.
4. Bower JH, Maraganore DM, Peterson BJ, Ahlskog JE, Rocca
WA. Immunologic diseases, anti-inflammatory drugs, and Parkinson disease: a case-control study. Neurology 2006;67:494–496.
5. Bower JH, Maraganore DM, McDonnell SK, Rocca WA. Incidence and distribution of parkinsonism in Olmsted County, Minnesota, 1976-1990. Neurology 1999;52:1214–1220.
6. Elbaz A, Peterson BJ, Yang P, et al. Nonfatal cancer preceding
Parkinson’s disease: a case-control study. Epidemiology 2002;13:
157–164.
7. Melton LJ, III. History of the Rochester Epidemiology Project.
Mayo Clin Proc 1996;71:266–274.
8. Sackett DL. Bias in analytic research. J Chronic Dis 1979;32:51–63.
9. Commission on Professional and Hospital Activities, National
Center for Health Statistics. H-ICDA, hospital adaptation of
ICDA, 2d ed. Ann Arbor, MI, 1973.
10. Katusic SK, Beard CM, Wiederholt WC, Bergstralh EJ, Kurland
LT. Incidence, clinical features, and prognosis in Bell’s palsy,
Rochester, Minnesota, 1968-1982. Ann Neurol 1986;20:622–627.
11. Braak H, Sastre M, Bohl JR, de Vos RA, Del Tredici K. Parkinson’s disease: lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre- and postganglionic neurons.
Acta Neuropathol 2007;113:421–429.
12. Paolino E, Granieri E, Tola MR, Panarelli MA, Carreras M. Predisposing factors in Bell’s palsy: a case-control study. J Neurol
1985;232:363–365.
13. Chen H, Jacobs E, Schwarzschild MA, et al. Nonsteroidal antiinflammatory drug use and the risk for Parkinson’s disease. Ann
Neurol 2005;58:963–967.
14. McGeer PL, McGeer EG. Inflammation and neurodegeneration in
Parkinson’s disease. Parkinsonism Relat Disord 2004;10 (Suppl
1):S3–S7.
1533
Vertical Optokinetic Nystagmus in
Parkinson’s Disease
Christopher M. Knapp, MD,1 Irene Gottlob, MD,1
Rebecca J. McLean, MD,1 Yusuf A. Rajabally, MD,2
Richard J. Abbott, MD,2 Suzanne Rafelt, BSc,3
and Frank A. Proudlock, PhD1*
1
Ophthalmology Group, Faculty of Medicine and Biological
Sciences, University of Leicester, Leicester Royal Infirmary,
Leicester, United Kingdom; 2Department of Neurology, University Hospitals of Leicester, Leicester General Hospital,
Leicester, United Kingdom; 3Department of Cardiovascular
Sciences, University of Leicester, Clinical Sciences Wing,
Glenfield Hospital, Leicester, United Kingdom
Abstract: Parkinson’s disease (PD) is associated with a
number of oculomotor deficits; however, little is known
about changes in vertical optokinetic nystagmus (OKN)
associated with PD. We recorded eye movements in 14
PD patients and 14 age-matched controls in response to
large field OKN stimulation using stimulus velocities of
208/second and 408/second. We compared asymmetry of
horizontal and vertical responses in the two groups. We
found vertical OKN to be strongly asymmetric in PD with
reduced gains for downward-moving stimuli. This asymmetry was significantly greater than that recorded in control volunteers. We postulate that this could result from
an abnormal pursuit/early OKN system in PD leading to
greater influence of the delayed OKN system. Ó 2009
Movement Disorder Society
Key words: optokinetic nystagmus; Parkinson’s disease;
asymmetry; eye movements; dopamine
Parkinson’s disease (PD), a neurodegenerative disorder characterized by loss of dopaminergic neurons in
the substantia nigra pars compacta, is associated with
several oculomotor deficits. These include diminished
ability in generating volitional saccades and in suppressing visually guided saccades with generation of
visually guided saccades less affected.1,2 Early studies
also suggest reduced responses in optokinetic nystagmus (OKN) and smooth pursuit gains,3–7 whereas
*Correspondence to: Dr. Frank Proudlock, Ophthalmology Group,
Faculty of Medicine and Biological Sciences, University of Leicester,
Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, PO Box 65, Leicester LE2 7LX, United Kingdom.
E-mail: fap1@le.ac.uk
Potential conflict of interest: Nothing to report.
Received 15 April 2008; Revised 26 March 2009; Accepted 27
March 2009
Published online 9 June 2009 in Wiley InterScience (www.
interscience.wiley.com). DOI: 10.1002/mds.22634
Movement Disorders, Vol. 24, No. 10, 2009
1534
C.M. KNAPP ET AL.
more recent studies suggest no differences to control
volunteers.8
The majority of studies into oculomotor deficits
associated with PD have investigated horizontal ocular
movements. A small number of studies have investigated vertical saccades and smooth pursuit9–11; however, little is known about the effect of PD on vertical
OKN (vOKN). In the clinic, OKN is usually tested
with the Barany drum, which stimulates a small area
of the visual field. Full-field stimulation biases
responses toward the subcortical component of OKN
because of greater stimulation of peripheral retina.12
In normals, most studies describe asymmetric vOKN
gain with preference for upward-moving stimuli13,14
although the literature is equivocal.15,16 The reasons
behind this are unclear although the asymmetric inputs
from upper and lower visual fields as we navigate
through space17 and/or from the otoliths resulting from
gravity13 have both been implicated. In addition, we
have recently shown that vOKN asymmetry is idiosyncratic with the degree and direction of asymmetry
remaining relatively consistent for a normal individual.18 In one previous study in 5 patients with PD, no
vOKN bias was observed.8 We have recorded horizontal (hOKN) and vOKN in a larger group of PD patients
comparing asymmetry of vOKN gains to age-matched
controls.
METHODS
Fourteen PD patients (11 men, 3 women, age range
35–85 years, mean 67.8 years) with a Hoehn & Yahr19
severity scale of 1–3 were recruited for the study along
with 14 age-matched healthy controls (6 men, 8
women, age range 43–83, mean 64.9 years). Patients
were recruited from neurology clinics in Leicester
General Hospital, UK. Diagnosis was made by a neurologist on the basis of at least two of three hemiparkinsonian syndromes of bradykinesia, rigidity, and/or
tremor. Thirteen of the 14 PD patients were on medication at time of testing (see Table 1 for medications).
There was no history of any known ophthalmological
or otological disorder in either group of subjects and
no known neurological abnormalities in the control
group. All subjects had normal eye movements (saccades and pursuit) when tested clinically. OKN was
not tested clinically. The study received local ethical
approval and was performed in accordance with tenets
of the declaration of Helsinki.
The OKN stimuli were projected onto a rear projection screen of 1.75 m width and 1.17 m height using a
VisLab projection system (SensoMotoric Instruments
Movement Disorders, Vol. 24, No. 10, 2009
TABLE 1. Clinical details of Parkinson’s patients including
Hoehn & Yahr grade (H & Y), duration of the disease, and
medications with levodopa equivalent dosage
Patients
Age
Sex
H&Y
Disease
duration
(yr)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
72
63
71
75
73
68
75
85
65
75
46
69
35
78
M
M
F
M
M
M
M
F
M
M
F
M
M
M
1.5
1
2
2
1.5
2.5
2
2
2
3
2
2
1
3
6
5
7
11
7
7
<1
4
6
7
7
7
<1
3
Medication
Levodopa
equiv
(mg)
L, C
L, P
L
L, P
L, R
L, R
L
L
R, T
L, C
L
L, P, C, A
Untreated*
L
1,100
1,200
300
500
600
300
300
750
NA
600
1,000
500
NA
200
L, levodopa; C, COMT inhibitor; P, Pergolide (dopamine agonist);
R, Ropinirole (dopamine agonist); T, Trihexyphenidyl (anticholinergic); A, Amantadine; NA, not applicable.
GmbH, Berlin) and Hitachi CP-X958 video projector
(1,024 3 768 resolution, 60 Hz). Eye movements were
recorded using a high-resolution pupil tracker at
250 Hz (EyeLink I, SensoMotoric Instruments). Calibration was achieved using nine fixation points, projected in a 3 3 3 grid (6208 wide, 617.58 high).
Recordings were converted offline to Spike2 neurophysiological software system files (Cambridge Electronic Design, UK) for subsequent analysis.
All subjects viewed the OKN stimuli binocularly at
1.2 m (resulting in a visual field of 6658 width and
6558 height). Head movements were minimized using a
chinrest, although the eye tracker provides head compensated gaze data. OKN eye movements were recorded
for a period of 15 seconds with a gap of at least 15 seconds between each test stimulus. The stimuli consisted
of a square wave-modulated contrast grating (spatial frequency 5 0.45 cycles/8) with Michelson contrast of 88%
(luminance from 0.88 to 14.3 cd/m2). The OKN response
was tested in four directions: upward, downward, leftward, and rightward in random order at linear velocities
of 208/seconds and 408/seconds. The volunteers were
encouraged to look toward the center of the screen
whilst keeping the stripes in focus.
Mean slow-phase velocity (MSPV) was calculated
from the total distance traveled/total time taken during
the slow phases. This method was used in preference
to the mean of each slow-phase velocity to prevent the
measurement from being distorted by short, less consistent, slow phases. The gain was the ratio of MSPV/
stimulus velocity. Mean beat frequency (the number of
VERTICAL OKN IN PARKINSON’S DISEASE
quick phases per second) was measured as mean reciprocal of the time between successive quick phases
uninterrupted by blinks.
Vertical and horizontal asymmetries were calculated
using the following formulae:
Vertical Asymmetry Index
¼
upward MSPV
upward MSPV þ downward MSPV
Horizontal Asymmetry Index
¼
rightward MSPV
rightward MSPV þ leftward MSPV
OKN gains, beat frequencies, and derived asymmetries were assumed to come from approximately normal distributions. Vertical and horizontal gains and
beat frequencies were compared separately in linear
mixed models including as fixed factors: group (i.e.,
PD vs. controls), stimulus direction (separate models
for upward vs. downward and rightward vs. leftward),
and speed (208/second vs. 408/second). The interaction
between group and stimulus direction was used to
explore differences in horizontal and vertical asymmetries between PD patients and controls. OKN asymmetry indices (gains and beat frequencies) were also compared using repeated measures two-way ANOVA
(where group and speed were fixed factors). Pearson’s
correlation was used to investigate the association
between severity of disease or levodopa equivalent and
OKN asymmetry.
RESULTS
Original eye movement recordings are shown in Figure 1A for a PD patient and control volunteer. Mean
OKN gains for each volunteer are presented with the
connecting lines indicating the degree of horizontal
asymmetry in Figure 1B and vertical asymmetry in
Figure 1C. The overall means for each direction are
shown above each chart in italics.
For vertical OKN gains, the interaction between
group and stimulus direction was highly significant
(F 5 8.29, P 5 0.0051) because of reduced responses
to downward stimulation compared with upward stimulation in PD patients but more equal responses in controls (see mean values on Fig. 1B). Stimulus direction
(F 5 17.25, P 5 8.1 3 1025, upward > downward
overall) and speed (F 5 64.4, P 5 6.7 3 10212, 208/
second > 408/second) were also significant factors but
group was not (F 5 0.69, P 5 0.41). For horizontal
1535
OKN gains, speed was the only significant factor (F 5
71.2, P 5 1.0 3 10212, 208/second > 408/second; F 5
0.16, P 5 0.69 for group; F 5 0.38, P 5 0.54 for
direction; and F 5 1.71, P 5 0.19 for group 3 direction). There were no significant effects of group or
direction on beat frequency in horizontal or vertical
directions (P > 0.1). However, lower speeds were significantly associated with higher vertical beat frequencies (F 5 12.1, P 5 0.0008).
Vertical and horizontal asymmetries were also compared for OKN gain (Fig. 1D) and beat frequency
(Fig. 1E). For gains, group was a significant effect on
vertical asymmetry (F 5 7.13, P 5 0.013, PD > controls) but not on horizontal asymmetry (F 5 1.17, P 5
0.29). Speed did not influence vertical (F 5 0.03, P 5
0.86) or horizontal (F 5 1.57, P 5 0.22) asymmetry
of gain. Neither group nor speed significantly influenced horizontal and vertical asymmetry of beat frequency (P > 0.05 for all factors).
The association between the severity of the disease
(Hoehn & Yahr scale) and mean vertical asymmetry of
gain was not significant (r 5 0.33, P 5 0.25) although
impairment of mean downward OKN gain at 408/seconds was near to significance (r 5 20.49, P 5 0.07).
There was also a near-significant negative trend
between the L-dopa equivalent of prescribed medication and mean vertical asymmetry of OKN gain (r 5
20.53, P 5 0.07), indicating that, if anything, increasing dosage removes the pattern of vertical asymmetry
associated with PD patients.
DISCUSSION
The main finding of this study is that PD results in a
consistent vOKN asymmetry with reduced responses to
downward-moving stimuli. This vOKN asymmetry is
stronger than that seen in age-matched controls.
The majority of literature in young healthy adults
also describes a vOKN preference for upward-moving
stimuli13,14 although there is some disagreement with
certain groups reporting either a downward preference16 or symmetrical OKN.8,15 Use of a full-field
stimuli and faster stimulus velocities tends to accentuate the upward preference. We have recently shown
that vOKN asymmetry is idiosyncratic, that is,
although between-subject variability is high, a certain
individual will tend to show a certain direction and
degree of vertical asymmetry.18 The reasons behind
this are unclear. vOKN asymmetry was not observed
in the control group in this study (although P 5 0.15
for 408/seconds). This could be due to using a nonfull-
Movement Disorders, Vol. 24, No. 10, 2009
FIG. 1. (A) Original eye movement recordings for a 65-year-old PD patient (Hoehn & Yahr 5 2) and a control volunteer of 68 years. Movements upward on the trace indicate either rightward or upward eye movements. Brisk OKN responses consisting of fast and slow phases can be
observed in all stimulus directions for the control volunteer and in rightward, leftward, and upward directions for the PD patient. A weak OKN
response to downward-moving stimuli was observed in the PD patient with less consistent fast and slow phases. Mean OKN gains are shown for
individual PD patients and controls in response to stimuli moving in (B) vertical and (C) horizontal directions. Connecting lines indicate the
degree of vertical and horizontal for each individual. PD patients showed strong vOKN asymmetry especially at 408/second. Means of all subjects
(with standard deviations in brackets) are shown in italics. Mean vertical and horizontal asymmetry indices for PD patients and controls are shown
for (D) OKN gain and (E) OKN beat frequency of the fast phases. Error bars 5 SEM, HAI 5 horizontal asymmetry indices, and VAI 5 vertical
asymmetry indices.
VERTICAL OKN IN PARKINSON’S DISEASE
field stimulus, slower stimulus velocities or possible
the use of an older age group. The change in vOKN
asymmetry with age has not been previously described.
The most interesting finding in this study is that PD
exaggerates vertical OKN asymmetry beyond that
observed in a normal control group.
The cause of vOKN asymmetry in either healthy
individuals or patients with PD is unclear. Asymmetric
sensory inputs from the visual field and otoliths have
both been implicated as the cause of physiological
vOKN asymmetry. The greater motion in the lower
visual field induced by forward motion such as walking
has been suggested may lead to reduced downward
OKN because of suppression of stimuli.17 Alternatively, evidence has accumulated that input from the
otoliths is important in generating vOKN asymmetry.13
OKN contains two components: an early component
(OKNe), which builds up and decays quickly and usually dominates the OKN response in humans; and a
delayed component (OKNd), which builds up and
decays much slower. The delayed component and in
particular its decay, called optokinetic afternystagmus
(OKAN), is highly asymmetric with a small response
following downward stimuli with the head in an
upright position.13,20 When otolith input is altered, e.g.,
in space, and when the head is either tilted or upside
down, OKAN and also of vOKN overall can become
symmetrical or reverse its asymmetry.13,20
One possibility is that the early OKN component in
PD is weaker compared with controls leading to
greater influence of the delayed OKN component
resulting in greater vOKN asymmetry. In support of
this, a number of studies suggest that the smooth pursuit system is deficient in PD.4–7 Because the pursuit
system shares similar neural circuitry to the early OKN
system, both may be affected by PD. In addition to the
basal ganglia, PD leads to changes in several structures
in the CNS, such as the cerebellum and occipital cortex, which could lead to vOKN asymmetry.21 Another
alternative is that the deficit may related to the generation of OKN quick phases. Quick phases are produced
by the premotor burst neurons in the rostral interstitial
nucleus of medial longitudinal fasciculus,22 which are
under the control of the superior colliculus and central
mesencephalic reticular formation. These all lie in
close proximity to the substantia nigra in the mesencephalon.
The possible confounding effects of medication are
unclear. L-dopa, for example, increases reflexive saccades latencies and reduces antisaccades errors.23 These
are associated with higher cortical processing, which
are however not directly related to OKN. Here, we
1537
show that increasing L-dopa equivalent dosage does not
lead to greater vertical asymmetry in OKN gain.
Acknowledgments: We thank the Ulverscroft Foundation
for their financial support.
Author Roles: Christopher M. Knapp: (1) Research project: A. Execution; (2) Statistical Analysis: A. Execution, B.
Review and Critique; (3) Manuscript: A. Writing of the first
draft, B. Review and Critique. Irene Gottlob: (1) Research
project: A. Conception, B. Organization; (2) Statistical Analysis: A. Review and Critique; (3) Manuscript: A. Review and
Critique. Rebecca J. McLean: (1) Research project: A. Organization, B. Execution. Yusuf A. Rajabally: (1) Research project: A. Conception, B. Execution; (3) Manuscript: A.
Review and Critique. Richard J. Abbott: (1) Research project:
A. Execution. Suzanne Rafelt: (2) Statistical Analysis: A.
Execution, B. Review and Critique. Frank A. Proudlock: (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 first
draft, B. Review and Critique.
REFERENCES
1. Chan F, Armstrong IT, Pari G, Riopelle RJ, Munoz DP. Deficits
in saccadic eye-movement control in Parkinson’s disease. Neuropsychologia 2005;43:784–796.
2. Vidailhet M, Rivaud S, Gouider-Khouja N, et al. Saccades and
antisaccades in parkinsonian syndromes. Adv Neurol 1999;80:
377–382.
3. Nakamura T, Kanayama R, Sano R, et al. Quantitative analysis
of ocular movements in Parkinson’s disease. Acta Otolaryngol
Suppl 1991;481:559–562
4. White OB, Saint-Cyr JA, Tomlinson RD, Sharpe JA. Ocular
motor deficits in Parkinson’s disease. III. Coordination of eye
and head movements. Brain 1988;111 (Part 1):115–129.
5. Rascol O, Clanet M, Montastruc JL, et al. Abnormal ocular
movements in Parkinson’s disease. Evidence for involvement of
dopaminergic systems. Brain 1989;112 (Part 5):1193–1214.
6. Waterston JA, Barnes GR, Grealy MA, Collins S. Abnormalities
of smooth eye and head movement control in Parkinson’s disease. Ann Neurol 1996;39:749–760.
7. Lekwuwa GU, Barnes GR, Collins CJ, Limousin P. Progressive
bradykinesia and hypokinesia of ocular pursuit in Parkinson’s
disease. J Neurol Neurosurg Psychiatry 1999;66:746–753.
8. Garbutt S, Riley DE, Kumar AN, Han Y, Harwood MR, Leigh RJ.
Abnormalities of optokinetic nystagmus in progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 2004;75:1386–1394.
9. Grant MP, Leigh RJ, Seidman SH, Riley DE, Hanna JP. Comparison of predictable smooth ocular and combined eye-head tracking behaviour in patients with lesions affecting the brainstem and
cerebellum. Brain 1992;115 (Part 5):1323–1342.
10. Rottach KG, Riley DE, DiScenna AO, Zivotofsky AZ, Leigh RJ.
Dynamic properties of horizontal and vertical eye movements in
parkinsonian syndromes. Ann Neurol 1996;39:368–377.
11. Vidailhet M, Rivaud S, Gouider-Khouja N, et al. Eye movements
in parkinsonian syndromes. Ann Neurol 1994;35:420–426.
12. Murasugi CM, Howard IP. Up-down asymmetry in human vertical optokinetic nystagmus and afternystagmus: contributions of
the central and peripheral retinae. Exp Brain Res 1989;77:183–
192.
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13. Clement G. A review of the effects of space flight on the asymmetry of vertical optokinetic and vestibulo-ocular reflexes. J Vestib Res 2003;13:255–263.
14. Ogino S, Kato I, Sakuma A, Takahashi K, Takeyama I. Vertical
optokinetic nystagmus in normal individuals. Acta Otolaryngol
Suppl 1996;522:38–42.
15. Baloh RW, Richman L, Yee RD, Honrubia V. The dynamics of
vertical eye movements in normal human subjects. Aviat Space
Environ Med 1983;54:32–38.
16. Schor C, Narayan V. The influence of field size upon the spatial
frequency response of optokinetic nystagmus. Vis Res 1981;21:
985–994.
17. Guedry FE, Benson A. Tracking performance during sinusoidal
stimulation of the vertical and horizontal semicircular canals. In:
Busdy DE, editor. Recent advances in aerospace medicine. Dordecht: Reidel Publishing Co; 1970. p 276–288.
18. Knapp CM, Gottlob I, McLean RJ, Proudlock FA. Horizontal
and vertical look and stare optokinetic nystagmus symmetry in
healthy adult volunteers. Invest Ophthalmol Vis Sci 2008;49:
581–588.
19. Hoehn MM, Yahr MD. Parkinsonism: onset, progression and
mortality. Neurology 1967;17:427–442.
20. Wei G, Lafortune SH, Ireland DJ, Jell RM. Human vertical optokinetic nystagmus and after-response, and their dependence upon
head orientation with respect to gravity. J Vestib Res 1994;4:37–47.
21. Hurley MJ, Jenner P. What has been learnt from study of dopamine receptors in Parkinson’s disease? Pharmacol Ther 2006;
111:715–728.
22. Horn AK, Buttner-Ennever JA. Premotor neurons for vertical eye
movements in the rostral mesencephalon of monkey and human:
histologic identification by parvalbumin immunostaining. J Comp
Neurol 1998;392:413–427.
23. Hood AJ, Amador SC, Cain AE, et al. Levodopa slows prosaccades and improves antisaccades: an eye movement study in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2007;78:565–
570.
Deep Brain Stimulation in
Dystonia: Sonographic Monitoring
of Electrode Placement into the
Globus Pallidus Internus
Uwe Walter, MD,1*,Alexander Wolters, MD,1
Matthias Wittstock, MD,1 Reiner Benecke, MD,1
Henry W. Schroeder, MD,2 and Jan-Uwe Müller, MD2
1
Department of Neurology, University of Rostock, Rostock,
Germany; 2Department of Neurosurgery, Ernst-Moritz-Arndt
University, Greifswald, Germany
Video
Abstract: Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is an effective treatment in primary
dystonia. Its success depends on the implantation accuracy of the DBS electrode into the targeted GPi. Discrepancies of up to 4 mm between the initial target, selected
on preoperative MRI, and the final DBS lead location are
caused mainly by caudal brain shift that occurs once the
cranium is open. Nowadays, transcranial sonography
(TCS) can display echogenic deep brain structures with
higher image resolution compared to MRI under clinical
conditions. Here, we demonstrate for the first time the
use of a contemporary clinical high-end TCS system for
intraoperative monitoring of DBS electrode position.
Herewith, a high-resolution real-time imaging of closely
located microelectrodes and of the DBS lead through the
intact skull is feasible. Simultaneous color-coded sonographic imaging of arteries near the anatomical
target allows further intraoperative refinement of DBS
lead positioning, simultaneously preventing hemorrhages.
Ó 2009 Movement Disorder Society
Key words: dystonia; deep brain stimulation; transcranial
sonography; globus pallidus internus
Deep brain stimulation (DBS) of the globus pallidus
internus (GPi) is an effective treatment in primary dystonia.1–3 Its success depends on the implantation accu-
Additional Supporting Information may be found in the online
version of this article.
*Correspondence to: Dr. Uwe Walter, Department of Neurology,
University of Rostock, Gehlsheimer Str, 20 D-18147, Rostock,
Germany. E-mail: uwe.walter@med.uni-rostock.de
Potential conflict of interest: The authors report no conflicts of
interest.
Received 30 January 2009; Revised 22 April 2009; Accepted 26
April 2009
Published online 1 June 2009 in Wiley InterScience (www.
interscience.wiley.com). DOI: 10.1002/mds.22663
Movement Disorders, Vol. 24, No. 10, 2009
SONOGRAPHY FOR DEEP BRAIN ELECTRODE PLACEMENT
1539
FIG. 1. Setting and typical images of intraoperative transcranial sonography (TCS) in a patient in whom deep brain stimulation (DBS) electrodes
were implanted bilaterally into the GPi. (A) Aspect of the patient with the head fixed in the stereotactic frame. The arrow denotes the access for
the ultrasound transducer. (B) Aspect of the patients head with inserted microelectrodes through the bore hole. The arrow denotes the position of
the ultrasound transducer. (C) Fusion image of preoperative MRI and corresponding intraoperative TCS scan parallel to the stereotactic trajectories (red and green lines). (D) Intraoperative TCS image corresponding to the fusion image in (C). The weakly echogenic thalami (T) and midbrain (M) are encircled for better recognition. (E) Intraoperative TCS image corresponding to the TCS image in (D). Two closely located microelectrodes are clearly visualized (arrows). Inserted panel in the left lower corner: photograph of the microelectrode. (F) Intraoperative TCS image
showing the tip of the final DBS lead (white arrow) and its distance to the posterior communicating artery (black arrow) and the perforating
branch to the GPi (blue arrow). Considering the previously determined imaging artefact of the DBS lead tip, monitoring of its distance to the perforating artery near the anatomical target allowed the intraoperative decision to slightly further insert the DBS lead for improvement of targeting
accuracy. Inserted panel in the left lower corner: photograph of the DBS lead.
racy of the DBS electrode array (‘‘lead’’) into the targeted GPi. Discrepancies of up to 4 mm (average 2
mm) between the initial target, selected on preoperative MRI, and the final DBS lead location are caused
mainly by caudal brain shift that occurs once the cranium is open.4 Intraoperative MRI may overcome targeting inaccuracy but is expensive and not widely
available.5
Transcranial sonography (TCS) allows real-time
gray-scale imaging of the brain through the intact skull
and, simultaneously, color-coded sonography (TCCS)
of basal cerebral arteries.6 Nowadays, TCS can display
echogenic deep brain structures with higher image resolution compared with MRI under clinical conditions.7
In patients with idiopathic generalized and segmental
dystonia, TCS depicts the GPi with abnormal increased
echogenicity,8,9 a finding caused by increased amounts
of copper and manganese.10–13 Here, we present first
results on the use of intraoperative TCS for electrode
placement into the GPi.
PATIENTS AND METHODS
Human Skull Phantom
For measuring the size of TCS imaging artefacts of
intracranial DBS lead, a human skull phantom with a
filling mimicking physical properties of brain tissue
was used as described earlier in detail.7 To detect possible heating during insonation, a thermo couple was
fixed to the DBS lead tip and connected to a digital
thermometer (metering precision, 0.1 centigrade).
Patients
After approval by the local ethics committee, intraoperative TCS was applied in two patients with primary
segmental dystonia refractory to conservative treatment
in whom DBS electrodes were implanted bilaterally
into the GPi. The first patient was a 38-year-old man
who suffered from segmental brachiofacial dystonia
with a severity of 15 points on the Tsui Rating Scale14
Movement Disorders, Vol. 24, No. 10, 2009
1540
U. WALTER ET AL.
and 27 points on the severity subscale of the Toronto
Western Spasmodic Torticollis Rating Scale (TWSTRS).15
The second patient was a 62-year-old woman who had
combined cervical dystonia, blepharospasm, and spasmodic dysphonia (Tsui Rating Scale, 6 points;
TWSTRS, 15 points). Both patients were preoperatively assessed for sufficient transcranial bone windows
to allow adequate TCS of deep brain structures.
Surgical Procedures
Surgical procedures were performed as described
previously,2 using a Leksell stereotactic head frame
(Fig. 1A). Using preoperative MRI, trajectories were
planned on an iPlan stereotactic planning station
(BrainLAB; Feldkirchen, Germany). In the operating
room, under monitored anaesthesia care, a 10-mm burr
hole was drilled and the dura opened (Fig. 1B). Using
guide tubes that terminated 35 to 40 mm superior to
the stereotactic target, five microelectrodes with a diameter each of 0.5 mm (Fig. 1E) were inserted serially.
After completion of the recordings and removal of the
microelectrodes, a Medtronic type 3,387 quadripolar
DBS lead (Medtronic, Inc., Minneapolis, MN) with a
diameter of 1.27 mm (Fig. 1F) was inserted down the
appropriate guide tube.
Intraoperative TCS
TCS was conducted under aseptic conditions through
the intact temporal (preauricular) skull employing the
clinical ultrasound system Acuson Antares (Siemens;
Erlangen, Germany) equipped with a 1.8–4.2 MHz
transducer (type PX4-1) (Fig. 1B). Parameter settings
were dynamic range 50 dB, postprocessing preset G.
Using the guide tubes at the stereotactic frame for
orientation, the transducer was twisted so that a
coronary brain section parallel to the trajectory was
displayed (Fig. 1C–E). Arteries near the GPi were
visualized on TCCS (Fig. 1F).
RESULTS
Phantom TCS Studies
Using the skull phantom, we found constant temperature (22.38C) of the intracranial DBS lead when
exposed to TCS or TCCS for 30 minutes each with
ultrasound frequencies of 2.0, 2.5, or 3.1 MHz (ultrasound intensity: mechanical index 1.4). In lateral direction of insonation, applied to monitor electrode depth,
the highly echogenic imaging artefact of the metal part
of the DBS lead was found to exceed the 1-mm rubber
Movement Disorders, Vol. 24, No. 10, 2009
tip by minimum 0.1 mm (range, 0.1–1.5 mm, depending on image brightness). In axial direction of insonation, the imaging artefact exceeding the real boundary
of the DBS lead was smaller (range, 0.3–0.6 mm;
resulting seeming DBS lead diameter, 1.9–2.5 mm,
depending on image brightness).
Intraoperative TCS Studies
In the intraoperative setting, the microelectrodes and
the final DBS lead were clearly visualized on TCS in
both patients (Fig. 1E, F; Video). The sizes of imaging
artefacts were equal to the sizes determined in the phantom studies. Bearing in mind that the imaging artefact
of the metal parts of the DBS lead exceeded the real
size of the 1-mm rubber tip by at least 0.1 mm, monitoring of its distance to the neighboring arteries allowed
the intraoperative decision to further insert the DBS
lead for improvement of targeting accuracy in our
patients (Fig. 1F; Video). In both patients, the bilateral
DBS lead tips were found on TCS to be located correctly in the GPi at nearly symmetric depth (right–left
difference, each, <2 mm) and distance from midline
(right–left difference, each, 0.7 mm).
Postoperative Outcome Measures
In agreement with the intraoperative TCS measures,
postoperative MRI showed the bilateral DBS lead tips
at correct position in the GPi at nearly symmetric
depth (right–left difference, patient 1, 1.0 mm; patient
2, 1.2 mm) and distance from midline (right–left difference, each, 0.5 mm). Clinical outcome was excellent in both patients. Dystonia severity assessed three
months after operation was markedly improved compared with preoperative assessment (improvement on
the Tsui rating scale and on the TWSTRS, Patient 1,
27%, 44%; Patient 2, 33%, 53%).14,15
DISCUSSION
We demonstrate, for the first time, the use of a clinical high-end TCS system for intraoperative monitoring
of DBS electrode position. Herewith, a high-resolution
real-time imaging of closely located microelectrodes
and of the DBS lead is feasible. Simultaneous TCCS
of arteries near the anatomical target allows further
intraoperative refinement of DBS lead positioning,
simultaneously preventing hemorrhages.
TCS has been reported earlier to allow intraoperative
documentation of DBS lead position in patients with
Parkinson’s disease.16 However, the imaging artefact of
the DBS lead has not been assessed, which poses mea-
SONOGRAPHY FOR DEEP BRAIN ELECTRODE PLACEMENT
suring accuracy of this early study in question. Moreover, the applied ultrasound system was a former-generation one with a considerably lower image resolution
compared to the system used in the present study.7
The risk of intraoperative hemorrhage due to targeting the GPi with electrodes has been related to diagnose of Parkinson’s disease rather than dystonia, presence of arterial hypertension, higher patient’s age,
larger diameter of microelectrodes, transventricular
electrode trajectories and increased number of microelectrode passes.17–19 It may well be that the usually
caudal brain shift during operation prevents higher
bleeding rates at the target site since the basal arteries
are located more caudally. Intraoperative TCCS enables more caudal positioning of the DBS lead to compensate for brain shift while monitoring its distance to
neighboring vessels. It should be stressed that, before
any application of TCS for intraoperative guiding the
positioning of DBS lead in patients, the sizes of imaging artefacts need to be estimated separately for each
different ultrasound system and each different DBS
lead type to account for differences of imaging technologies and lead shape.
We conclude that high-end TCS is easily feasible
during stereotactic surgery. In combination with stereotactic X-ray images, it enables the refinement and the
documentation of the correct position of implanted GPi
electrodes in real time.
Acknowledgments: The authors thank Wolfgang
Roßmannek, director of the Media Design Center at Rostock
University, for technical realization of the accompanying
video.
Author Roles: Uwe Walter: Research project, conception,
organization and execution. Manuscript, writing of the first
draft. Video, design; Alexander Wolters: Research project,
conception and execution. Manuscript, review and critique.
Video, design; Matthias Wittstock: Research project, conception and execution. Manuscript, review and critique; Reiner
Benecke: Research project, conception and organization.
Manuscript, review and critique; Henry W. Schroeder:
Research project, organization. Manuscript, review and critique; Jan-Uwe Müller: Research project, conception, organization and execution. Manuscript, review and critique.
1541
3. Mueller J, Skogseid IM, Benecke R, et al. Pallidal deep brain
stimulation improves quality of life in segmental and generalized
dystonia: results from a prospective, randomized sham-controlled
trial. Mov Disord 2008;23:131–134.
4. Khan MF, Mewes K, Gross RE, Skrinjar O. Assessment of brain
shift related to deep brain stimulation surgery. Stereotact Funct
Neurosurg 2008;86:44–53.
5. Hall WA, Truwit CL. Intraoperative MR-guided neurosurgery.
J Magn Reson Imaging 2008;27:368–375.
6. Walter U, Behnke S, Eyding J, et al. Transcranial brain parenchyma sonography in movement disorders: state of the art. Ultrasound Med Biol 2007;33:15–25.
7. Walter U, Kanowski M, Kaufmann J, Grossmann A, Benecke R,
Niehaus L. Contemporary ultrasound systems allow high-resolution transcranial imaging of small echogenic deep intracranial structures similarly as MRI: a phantom study. Neuroimage 2008;40:
551–558.
8. Naumann M, Becker G, Toyka KV, Supprian T, Reiners K. Lenticular nucleus lesion in idiopathic dystonia detected by transcranial sonography. Neurology 1996;47:1284–1290.
9. Becker G, Naumann M, Scheubeck M, et al. Comparison of
transcranial sonography, magnetic resonance imaging, and single
photon emission computed tomography findings in idiopathic
spasmodic torticollis. Mov Disord 1997;12:79–88.
10. Becker G, Berg D, Rausch WD, Lange HK, Riederer P, Reiners
K. Increased tissue copper and manganese content in the lentiform nucleus in primary adult-onset dystonia. Ann Neurol
1999;46:260–263.
11. Berg D, Weishaupt A, Francis MJ, et al. Changes of coppertransporting proteins and ceruloplasmin in the lentiform nuclei in
primary adult-onset dystonia. Ann Neurol 2000;47:827–830.
12. Walter U, Krolikowski K, Tarnacka B, Benecke R, Czlonkowska
A, Dressler D. Sonographic detection of basal ganglia lesions in
asymptomatic and symptomatic Wilson disease. Neurology 2005;
64:1726–1732.
13. Walter U, Dressler D, Lindemann C, Slachevsky A, Miranda M.
Transcranial sonography findings in welding-related Parkinsonism in
comparison to Parkinson’s disease. Mov Disord 2008;23: 141–145.
14. Tsui JK, Eisen A, Stoessel AJ, Calne S, Calne DB. Double-blind
study of botulinum toxin in spasmodic torticollis. Lancet 1986;2:
245–247.
15. Consky ES, Lang AE. Clinical assessments of patients with cervical dystonia. In: Jankovic J, Hallett M, editors. Therapy with
botulinum toxin. New York: Marcel Dekker; 1994. p 211–237.
16. Moringlane JR, Fuss G, Becker G. Peroperative transcranial sonography for electrode placement into the targeted subthalamic
nucleus of patients with Parkinson disease: technical note. Surg
Neurol 2005;63:66–69.
17. Binder DK, Rau GM, Starr PA. Risk factors for hemorrhage during microelectrode-guided deep brain stimulator implantation for
movement disorders. Neurosurgery 2005;56:722–732.
18. Sansur CA, Frysinger RC, Pouratian N, et al. Incidence of symptomatic hemorrhage after stereotactic electrode placement. J Neurosurg 2007;107:998–1003.
19. Ben-Haim S, Asaad WF, Gale JT, Eskandar EN. Risk factors for
hemorrhage during microelectrode-guided deep brain stimulation
and the introduction of an improved microelectrode design. Neurosurgery 2009;64:754–762.
REFERENCES
1. Vidailhet M, Vercueil L, Houeto JL, et al. Bilateral deep-brain
stimulation of the globus pallidus in primary generalized dystonia. N Engl J Med 2005;352:459–467.
2. Kupsch A, Benecke R, Müller J, et al. Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N Engl J
Med 2006;355:1978–1990.
Movement Disorders, Vol. 24, No. 10, 2009
1542
P. SCHWINGENSCHUH ET AL.
Tremor on Smiling
Petra Schwingenschuh, MD,1,3 Carla Cordivari, MD,2
Julia Czerny, MD,1 Marcello Esposito, MD,2
and Kailash P. Bhatia, MD1*
1
Sobell Department of Motor Neuroscience and Movement
Disorders, UCL, Institute of Neurology, Queen Square,
London, United Kingdom; 2Neurophysiology Department,
The National Hospital for Neurology and Neurosurgery,
Queen Square, London, United Kingdom; 3Medical
University of Graz, Department of Neurology, Austria
Video
tremor.2 Also a number of drugs, most prominently
neuroleptics have been reported to cause orolingual
tremors.3
Task- or position-specific orolingual tremors occur
exclusively during specific positions or tasks.1,2
Although such tremors have been well described to
occur during speaking, drinking, or playing a wind
instrument,1 so far only one case of a smiling induced
tremor was reported in the literature.4
Here, we describe two patients, who present with a
tremor involving facial muscles and appearing only on
smiling or other activation of the risorii muscles.
CASE REPORTS
Abstract: Facial tremor occurring on smiling is a rare
phenomenon and has been described (to the best of our
knowledge) in the literature only once. We describe two
patients who presented with a bilateral facial tremor
that occurred only on smiling and other activation of
the risorii muscles and had a high frequency of 9 Hz.
One patient additionally suffered from young-onset
Parkinson’s disease, whereas the other had no further
neurological symptoms or signs apart from this tremor.
Anti-parkinsonian medication was unhelpful for the facial
tremor in the patient with Parkinson’s disease. Tremor
on smiling may be a discrete entity or may be associated
in some cases of Parkinson’s disease.
Ó 2009 Movement Disorder Society
Key words: orolingual tremor; facial tremor; task-specific
tremor; smiling
Together with tremors of the jaw, tongue, and pharynx, tremors involving the face are part of the spectrum of orolingual tremors and have been described
with a number of conditions.1 Jaw tremor is a relatively common feature in Parkinson’s disease (PD) and
also occurs predominantly as activation-induced tremor
in the context of primary or secondary oromandibular
dystonia.1 Isolated tremors of orolingual structures in
the context of classical essential orolingual tremor
occur very rarely and this diagnosis should only be
considered if there is an associated postural upper limb
Additional Supporting Information may be found in the online
version of this article.
*Correspondence to: Dr K.P. Bhatia, Sobell Department, Institute
of Neurology, UCL, Queen Square, London, UK, WC1N 3BG.
E-mail: k.bhatia@ion.ucl.ac.uk
Potential conflict of interest: None reported.
Received 28 October 2008; Revised 2 April 2009; Accepted 26
April 2009
Published online 1 June 2009 in Wiley InterScience (www.
interscience.wiley.com). DOI: 10.1002/mds.22666
Movement Disorders, Vol. 24, No. 10, 2009
Case 1
This 42-year-old man developed tremor and stiffness
of the left arm at age 35. On examination at age 39, he
showed clear signs of parkinsonism with a hypomimic
face and a resting tremor mainly of the left arm (frequency 3–5 Hz). In addition, he had a high frequency
tremor of the face induced by smiling (see supporting
information video) and activation of the risorii muscles
by grimacing. He had noticed this tremor on smiling
many years prior to the onset of the left arm tremor
and it caused social discomfort. There was no response
to alcohol and no relevant family history. In view of
the slightly unusual features, other causes of parkinsonism were excluded before a diagnosis of young-onset
PD was made. Full blood count, liver function, and
thyroid function tests as well as copper and ceruloplasmin levels were within normal limits. In addition, he
was tested negative for SCA 1, SCA 2, SCA 6, SCA
7, and PARKIN gene mutations. Neurophysiological
findings are described below. His parkinsonian symptoms including the limb tremor responded well to a
combination of selegiline (10 mg/day) and ropinirole
(15 mg/day), but had no effect on his tremor on smiling. Also a trial of levodopa (300 mg/day) made no
difference and he did not wish to try botulinum toxin
injections at this stage.
Case 2
This 61-year-old woman was referred with an
8-month history of facial tremor induced by smiling.
She first attributed this to a prolonged course of steroids prescribed for chronic eczema, however, the
tremor continued after the steroids were stopped. There
was no postural limb tremor, no family history and no
alcohol benefit. On examination, she had a mild bilateral high frequency tremor of the cheeks, more pro-
TREMOR ON SMILING
nounced on the right side, when she was asked to
smile (see Supporting Information video) or to activate
the risorii muscles by grimacing. The remainder of her
neurological examination was unremarkable. A brain
magnetic resonance imaging excluded any brainstem
pathology. All blood tests including voltage-gated
potassium channel antibodies, anti-acetylcholine receptor antibodies, and anti-GAD antibodies were negative.
Neurophysiological findings are described below. In
view of the rather static picture of the condition and
no evidence of any underlying degenerative disease
process a diagnosis of benign action-induced facial
tremor was made. Botulinum toxin injections were
refused at this stage due to the possible side effect of
facial drooping.
Neurophysiological Assessment
We performed accelerometry from the lower parts of
each orbicularis oculi muscle and needle electromyogram (EMG) recordings from the orbicularis oculi and
risorii muscles bilaterally. EMG activity and accelerometry were recorded simultaneously and continuously
for 4 minutes at rest and 30 seconds for each facial
movement studied: pursing the lips, speaking, raising
the nose, and smiling with moderate and maximum
effort. The main findings are summarized in Figure 1.
Both patients had normal EMG recordings at rest without myokymic discharges. EMG during smiling at a
moderate and steady level of contraction revealed
rhythmic synchronous bursts of 70 to 85 ms duration
in the orbicularis oculi and risorii muscles bilaterally
in both patients. The EMG bursts appeared almost
immediately on smiling and were associated with a
visible facial tremor. EMG bursts and symptoms disappeared with forceful smiling indicating that a certain
level of contraction effort (motor unit recruitment) was
required for tremor production. In both patients tremor
was absent during all other facial movements studied.
Power spectrum analysis from EMG and accelerometry
recordings during smiling with moderate effort
revealed very sharp frequency peaks just above 9 Hz.
These 9 Hz range oscillations were very strongly
coherent between all combinations of pairs of muscles
indicating a common drive.
DISCUSSION
Here, we have described two patients with an
action-induced facial tremor involving mainly the
cheeks and occurring only on smiling (which was the
patients’ main complaint) or other activation of the
risorii muscles such as grimacing. The two cases show
1543
some differences as patient one additionally suffers
from young-onset PD, whereas the other patient shows
no evidence of any other neurological disease. In both
patients, the facial tremor had a high frequency of just
over 9 Hz.
This ‘‘tremor on smiling’’ may be a discrete entity.
It did not resemble the classical orolingual parkinsonian tremor in that it did not occur at rest or together
with a limb tremor in our PD patient, it was unresponsive to antiparkinsonian medication, and of course a
similar tremor was seen in case 2 who did not show
any symptoms or signs of PD.
Jacome and Yanez4 described a case of a 27-yearold woman who presented with a 9-year history of a 5
to 6 Hz perioral facial tremor (EMG burst duration
75–125 ms) induced by spontaneous smiling or volitional contraction of the risorii muscles. She had no
detectable neurological disorder otherwise associated
with facial tremor, her father seemed to have suffered
from the same symptom, and she responded well to
propranolol, so this ‘‘tremor of the smile’’ was suggested to represent a form of familial essential tremor.
Our two cases resembled the one described above as
the facial tremor was only present at a moderate level
of contraction of the risorii muscles and was abolished
with forceful smiling. Distinguishing features, however,
were a considerably higher tremor frequency and a
shorter duration of EMG bursts (70–85 ms) in our two
cases, which lies in the range of burst durations typically seen in other higher frequency tremors such as
essential tremor (75–100 ms) and orthostatic tremor
(around 60 ms).5,6
Conditions that may mimic facial tremor and cause
diagnostic confusion include facial myoclonus.1 Lou
et al. described facial action myoclonus in four patients
with olivopontocerebellar atrophy.7 Their patients had
facial myokymic discharges at rest and irregular
arrhythmic (approximately 9 Hz) EMG bursts of short
duration (10–75 ms) in the bilateral orbicularis oris
and risorii muscles at the onset of muscle contraction,
that became more rhythmic with a very high frequency
of around 25 Hz during maximum muscle contraction.
The electrophysiological recordings in our two patients
are different as they had no myokymic discharges at
rest, and EMG bursts induced by smiling in our
patients were highly regular and rhythmic at a stable
frequency of around 9 Hz. In our opinion, the electrophysiological findings in our patients are suggestive of
tremor rather than myoclonus.
None of our patients with a tremor on smiling had
evidence of dystonia in the orolingual region or any
other body part, hence this cannot be classified as
Movement Disorders, Vol. 24, No. 10, 2009
1544
P. SCHWINGENSCHUH ET AL.
FIG. 1. Accelerometry and needle electromyography (EMG) recordings from the orbicularis oculi and risorii muscles at rest in case 1 (A) and
case 2 (D) showing normal EMG activity and no tremor. Smiling with moderate effort of contraction induced synchronous EMG bursts at a
frequency of about 9 Hz (burst duration 70–85 ms) in patient 1 (B) and patient 2 (E). The spectra of the left risorii muscles (G, patient 1, J,
patient 2) and the spectra of the left sided accelerograms (H, patient 1, K, patient 2) under this condition showed a sharp peak at just above 9
Hz; EMG-EMG coherence analysis during moderate smiling revealed a common drive for the right and left risorius in case 1 (I) and case 2 (L)
with a peak of coherence just above 9 Hz. Tremor is suppressed by maximum effort of contraction of risorii muscles (C, patient 1, F, patient 2).
Abbreviations: Acc, accelerometer, R, right, L, left, Ris, risorius muscle, Ooc, Orbicularis oculi muscle.
‘‘dystonic tremor’’ or ‘‘tremor associated with dystonia".2,8 None of our patients had been exposed to any
causative drugs prior to the onset of the tremor. Other
Movement Disorders, Vol. 24, No. 10, 2009
conditions causing abnormal facial movements including myokymia as seen in multiple sclerosis9 or neuromyotonia10 and oculomasticatory myorhythmia as seen
TREMOR ON SMILING
in Whipple’s disease11 can also be excluded since
none of these disorders would present solely with
smile-induced very rhythmic, high frequency, oscillatory movements of the cheeks.
Finally, fast tremors above 9 Hz are unlikely to be
non-organic and suggest a central oscillator as a generator of tremor.12 Orthostatic tremor is an example of a
high frequency tremor occurring only on standing and
is thought to arise from a central oscillator that may be
located in the posterior fossa.13 The exact origin of the
tremor on smiling is uncertain but it may also arise
from a brainstem/cerebellar loop oscillator.
Management of the tremor on smiling could not be
sufficiently achieved with antiparkinsonian medication
in the patient with PD, and both patients were reluctant
to try medication useful in other forms of tremor such
as propranolol, tetrabenazine, or benzodiazepines. Due
to the possibility of side effects with facial muscular
weakness they were also not inclined to try botulinum
toxin injections, which have been shown to be beneficial in jaw tremor related to PD.14
We believe that this form of tremor should be recognized and encourage others with a similar experience
to describe their findings. It would be interesting to see
whether this tremor on smiling is a rare and possibly
early symptom of PD or whether it exists as a discrete
entity.
LEGENDS TO THE VIDEO
Segment 1. This video shows a 42-year-old gentleman with young-onset PD (case 1). He is currently on
medication (ropinirole 15 mg/day, selegiline 10 mg/
day). Smiling and activation of the risorii muscles
induces a bilateral high-frequency tremor of the
cheeks. The tremor subsides when the muscles are
relaxed. He has mild bradykinesia, more so on the left
side and reduced left-sided arm swing when walking
and no limb tremor.
Segment 2. This woman (case 2) has no limb tremor
at rest or on keeping her arm outstretched and no facial
tremor. However, on smiling a high frequency facial
tremor appears more pronounced on the right side
involving the cheeks and upper angle of the mouth
1545
(seen on supporting information video between 50 sec
and 1:00 min). There were no other neurological signs.
Finanical Disclosure: Petra Schwingenschuh has
been funded by the Austrian Science Fund (FWF,
Erwin Schroedinger Grant).
Author Roles: P Schwingenschuh: Project execution,
writing of manuscript and revisions, review and critique.
C Cordivari: Electrophysiological studies, review and
critique. J Czerny: Writing of a first draft. M Esposito:
Electrophysiological studies. K Bhatia: project conception,
organization, execution, review and critique.
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