Adult onset asymmetric upper limb tremor misdiagnosed as
Parkinson’s disease: A clinical and electrophysiological study
Petra Schwingenschuh, MD
1,5
, Diane Ruge, MD
1
, Mark J Edwards, PhD
1
, Carmen
Terranova, MD
1
, Petra Katschnig, MD
1,5
, Fatima Carrillo, MD
2
, Laura Silveira-Moriyama,
MD
3
, Susanne A Schneider, PhD
1
, Georg Kägi, MD
1
, John Dickson, PhD
4
, Andrew J Lees,
MD
3
, Niall Quinn, MD
1
, Pablo Mir, PhD
2
, John C Rothwell, PhD
1
, and Kailash P Bhatia,
MD
1
1
Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology,
UCL, Queen Square, London, UK
2
Unidad de Trastornos del Movimiento, Servicio de Neurología, Instituto de Biomedicina de
Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, CIBERNED. Seville,
Spain
3
Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, London, UK
4
Institute of Nuclear Medicine, UCL, London, UK
5
Department of Neurology, Medical University Graz, Austria
Summary
Approximately 10% of subjects thought clinically to have early Parkinson’s disease (PD) have
normal dopaminergic functional imaging (SWEDDs – Scans Without Evidence of Dopaminergic
Deficit). SWEDDs are a heterogeneous group. Here we aimed to delineate clinical and
electrophysiological characteristics of a distinct subgroup of SWEDDs patients from PD and to
clarify the underlying pathophysiology of this subgroup as a form of parkinsonism or dystonia.
Therefore we compared clinical details of 25 patients referred with a diagnosis of tremor-dominant
PD but with normal DaT SPECT scans (SWEDDs) with 12 tremor-dominant PD patients with
abnormal DaT SPECT scans. We performed tremor analysis using accelerometry in the following
patients with 1) SWEDDs, 2) PD, 3) primary segmental dystonia with dystonic limb tremor and 4)
essential tremor (ET). We used transcranial magnetic stimulation with a facilitatory paired
associative stimulation (PAS) paradigm to test if sensorimotor plasticity in SWEDDs resembled
the pattern seen in PD, dystonia or ET. Although PD and SWEDDs patients shared several clinical
features, the lack of true bradykinesia, occurrence of dystonia, and position- and task-specificity of
tremor favoured a diagnosis of SWEDDs, whereas re-emergent tremor, true fatiguing or
decrement, good response to dopaminergic drugs as well as presence of nonmotor symptoms made
PD more likely. Basic tremor parameters overlapped between SWEDDs, PD, segmental dystonia
and ET. However, a combination of re-emergent tremor and highest tremor amplitude in the
resting condition was characteristic of PD tremor, while SWEDDs, dystonia and ET subjects had
the highest tremor amplitude during action. Both SWEDDs and segmental dystonia patients
exhibited an exaggerated pattern of sensorimotor plasticity in response to the PAS paradigm, with
spread of excitation to an adjacent hand muscle. In contrast, PD patients showed no response to
PAS, and the response of ET patients was no different from controls. Taken together, these results
Correspondence to: Prof. KP Bhatia, Sobell Department, Institute of Neurology, UCL, Queen Square, London, WC1N 3BG, UK, Tel:
+44 207 837 3611 ext 4253, Fax: +44 207 676 2175, k.bhatia@ion.ucl.ac.uk.
UKPMC Funders Group
Author Manuscript
Mov Disord. Author manuscript; available in PMC 2010 December 3.
Published in final edited form as:
Mov Disord. 2010 April 15; 25(5): 560–569. doi:10.1002/mds.23019.
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may help differentiate these SWEDDs patients from PD and support our hypothesis that adult-
onset dystonia is the underlying diagnosis in this sub-group of patients with SWEDDs.
Keywords
SWEDDs; benign tremulous Parkinson’s disease; dystonic tremor; accelerometry; paired
associative stimulation
Introduction
Recent drug trials in idiopathic Parkinson’s disease (PD) have used functional dopaminergic
imaging ([
18
F]dopa PET, DaT SPECT) as surrogate markers of disease progression. An
unexpected consequence of this study design has been that 4%-14.7% of recruited patients,
all of whom apparently fulfilled clinical diagnostic criteria for PD, had normal dopaminergic
functional imaging ((Marek and Seibyl, 2003; Whone et al., 2003). These individuals have
been referred to as having SWEDDs (“Scans without evidence of dopaminergic deficit”).
There has been considerable debate as to the exact diagnosis in these patients; could they
have very early PD, some previously unrecognized form of PD, or not have PD at all? The
latter possibility seems most likely given that these patients failed to respond to levodopa in
the ELLDOPA study (Fahn, 2005) and repeat dopamine transporter scans after an interval of
4 years in a proportion of patients still showed no nigrostriatal degeneration (Marek et al.,
2005). SWEDDs are a heterogeneous group, and alternative diagnoses that have been
suggested include essential tremor (ET), depression, vascular or psychogenic parkinsonism,
dopa-responsive dystonia, and rare causes of supranigral parkinsonism (Fahn, 2005).
We have previously reported a small clinical case series of 10 patients with SWEDDs.
(Schneider et al., 2007). These patients had all been referred with a diagnosis of PD and had
asymmetric resting arm tremor as their dominant feature, as well as increased muscle tone,
impaired arm swing and sometimes also facial hypomimia and jaw tremor. We identified
signs of dystonia, or components of their arm tremor that were compatible with dystonic
tremor and hence made the suggestion that this group had primary adult-onset dystonic
tremor and that this entity may be one cause of SWEDDs.
There are a number of potential criticisms of this proposition. Firstly, there is no definite
diagnostic test for dystonia/ dystonic tremor and the diagnosis of dystonia depends entirely
on clinical acumen. The dystonic features we described in our previous group of 10 patients
were subtle in some cases and more importantly, they were not assessed by a clinician
blinded to the results of the DaT SPECT scans (Schneider et al., 2007). Dystonia is also
known to be a feature of PD itself (particularly in those with young disease onset), and
therefore its presence does not automatically indicate a diagnosis of primary dystonia. More
recently, a group of SWEDDs subjects was reported to have a normal sense of
smell(Silveira-Moriyama et al., 2009). These patients have not yet been compared with PD
patients regarding other non motor symptoms. Also, apart from the normal dopamine
transporter scans, there has been no attempt to investigate in detail the pathophysiology of
this condition and in particular no use of experimental methods that might help to
distinguish PD from dystonia. The tremor characteristics of these patients have not been
compared with PD, clinically definite dystonic tremor or essential tremor (ET). Also, one
would predict that if these patients have dystonia that their response to a plasticity probing
protocol, such as paired associative stimulation (PAS), might be different from PD. The
dynamic changes observed in motor cortex after PAS represent a form of motor cortex
plasticity (Stefan et al., 2000; Wolters et al., 2003; Wolters et al., 2005). In healthy subjects
plasticity induced by PAS evolves rapidly (within 30 min), is persistent (minimum duration
Schwingenschuh et al. Page 2
Mov Disord. Author manuscript; available in PMC 2010 December 3.
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