Movement Disorders

Vol. 17, No. 5, 2002, pp. 11151142

2002 Movement Disorder Society

Abstracts

Fourth International Dystonia Symposium

INTRODUCTION
Report on the Fourth International Dystonia Symposium

Stanley Fahn, MD1* Mark Hallett, MD,2 and Mahlon DeLong, MD3
1
Department of Neurology, Columbia University College of Physicians and Surgeons, and the Neurological Institute
of New York, Presbyterian Hospital, New York, New York, USA
2
National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA
3
Emory University, Atlanta, Georgia, USA

The Fourth International Dystonia Symposium, sponsored by the Dystonia Medical

Research Foundation and the National Institutes of Health, was held in Atlanta, Georgia,
on June 1315, 2002. In addition to 24 invited plenary speakers, there were peer-reviewed,
abstract-accepted scientific platform (n 27) and poster (n 13) presentations. The six
thematic sessions of the symposium were: pathophysiology, Oppenheims dystonia, other
genetic dystonias, PET scans and biochemistry of dystonia, musicians and other focal
dystonias, and therapeutics. In addition, the participants spent an exciting evening viewing
and discussing videotapes of different genetic forms of dystonia. This brief synopsis does
not do justice to the comprehensive reviews, updates, new scientific disclosures, and
discussions that took place during the symposium. Only a few of the highlights can be
included here, and interested readers are encouraged to immerse themselves into the
detailed proceedings that will be published in an upcoming monograph in the Advances in
Neurology series.
Mark Hallett presented a review on the loss of neural inhibition causing the abnormal
movements of dystonias, and suggested that the problem in dystonia was specifically a
loss of surround inhibition. Ryuji Kaji described findings of sensory deficits in dystonia
whereby distortion of sensory feedback may play a pathophysiological role. Nancy Byl
reviewed her experimental work on primates, who developed focal dystonia apparently due to
aberrant neuroplasticity as a result of repetitive motor performance. She proposed that faulty
learning created an altered sensorimotor cortical representation of the hand, and that appro-
priately designed learning tasks could normalize the representation and treat the dystonia.
Sarah Augood discussed the GAG deletion in the DYT1 gene for the protein TorsinA
that causes Oppenheims dystonia. Synthesis of this protein appears to be greatest in
dopamine neurons in the substantia nigra, but is found in many other regions in the brain.
Brett Lauring described how TorsinA is in the lumen of the endoplasmic reticulum and
may play a role in unfolding altered and misfolded proteins. This process requires energy,
and TorsinA has ATPase activity.
Marie-Franoise Chesselet followed the developmental pattern of TorsinA in rats, using
antibodies against the proteins. A distinctive pattern was found whereby the protein
reached its peak in cholinergic striatal neurons in young rats, proportional to the age that
young children develop Oppenheims dystonia. William Dauer described mice with either
knock-out or knock-in alterations of the DYT1 gene. The mice did not display any obvious
abnormal involuntary movements, but they were significantly impaired in rotarod perfor-

1115
1116 4th INTERNATIONAL DYSTONIA SYMPOSIUM

mance. The dopaminergic system of these mice appeared normal. A considerable amount
of information is accumulating about TorsinA biology, but how its alteration causes
dystonia is still obscure.
Susan Bressman led off the session on other genetic forms of torsion dystonia and
reviewed their clinical phenotypes and inheritance patterns.
Laurie Ozelius then reviewed what is known about the molecular genetics of DYT6, 7,
12 and 13, and Thomas Gasser described his finding that the genetic mutation for
myoclonus-dystonia is in the gene for the protein epsilon-sarcoglycan (SGCE). How an
altered (SGCE) causes the phenotype is unknown. Ozelius has found this genetic alter-
ation in other families with myoclonus-dystonia. Rachel Saunders-Pullman studied non-
dystonic symptoms in the various genetic dystonias, finding obsessivecompulsive per-
sonality and alcoholism in many patients with myoclonus dystonia. She also looked at
factors such as maternal imprinting, gender and environmental conditions that could
contribute to the incomplete penetrance seen with many of the genetic dystonias including
Oppenheims dystonia. Yoskiaki Furukawa reviewed the molecular genetics and the brain
biochemistry of dopa-responsive dystonia (DRD). About 40% of patients with DRD do
not have a mutation in the coding region of GTP cyclohydrolase 1 on chromosome 14q22,
so the genetics of this disorder has not been solved completely. Also there is loss of
tyrosine hydroxylase protein in striatum, which needs explanation. Diagnostic screening
by CSF analysis of compounds in the biopterin pathway may be helpful in determining the
diagnosis. Andrew Singleton summarized the status of the search for the gene for lubag
(X-linked dystoniaparkinsonism) seen primarily in Filipino men. The gene has not yet
been identified, and more patients are needed. It is likely that more genes for the different
dystonias will be identified in the near future.
David Eidelberg utilized FDG PET scanning to study nonmanifesting carriers of the
mutated DYT1gene and found that motor sequence learning tasks are associated with an
altered activation of brain regions, from frontal to posterior parietal cortical areas. Joel
Perlmutter utilized dopaminergic receptor ligands with PET and concluded that the D2
receptor pathway in the basal ganglia is impaired. Alan Crossman investigated the levodopa-
induced dystonia model in MPTP-lesioned, nonhuman primates and tested a number of
pharmaceutical agents for their ability to alleviate the dystonia. Although some agents were
effective in these animal models, this has not been the case in patients with dystonia.
Steven Frucht reviewed musicians dystonia, particularly embouchure dystonia, i.e.
involving perioral muscles of the lower face, used to control the force and direction of
airflow into the mouthpiece of a woodwind or brass instrument. Michael Charness found
that musicians with task-specific focal dystonia show abnormalities in sensory processing
and sensorimotor integration. Eckart Altenmuller analyzed the clinical characteristics of
musicians with dystonia and found that keyboard instrumentalists with dystonia were
affected predominantly in the right hand, as were those utilizing plucking instruments,
while string players displayed predominantly left hand dystonia. Alberto Priori found
immobilization of the affected limb to be successful in overcoming musicians cramp, but
only in those individuals affected for a short time.
The therapeutics session reviewed available therapies, including medications, botuli-
num toxin, and recent surgical approaches, including pallidotomies and pallidal stimula-
tion. There was consensus that patients with primary dystonia have a better outcome with
surgery than those with secondary dystonia. There is no good explanation as to why
patients might have a delay of benefit after surgery, and why the benefit may be lost after
several years. Physiological recordings during surgery reveal altered firing patterns in the
pallidum, but why surgery at this target can alleviate dystonia remains unclear. There is
still uncertainty as to the ideal patient for surgery, the best target, the degree of benefit,
the duration of benefit, and the adverse effects for the various surgical procedures. More
work and careful observations are required.

Movement Disorders, Vol. 17, No. 5, 2002

 4th INTERNATIONAL DYSTONIA SYMPOSIUM
I. PATHOPHYSIOLOGY
Dystonia: Abnormal Movements Result from Loss of Inhi-
bition
M. Hallett
Human Motor Control Section, NINDS, National Institutes of
Health, Bethesda, Maryland, USA
Dystonia is characterized by excessive movement, and this is
likely due to a loss of inhibition. This review argues that the
defective inhibition in dystonia is surround inhibition, which
is the suppression of unwanted movements. Evidence in favor
of decreased inhibition in dystonia includes deficient reciprocal
inhibition, less inhibition in the blink recovery curve, reduced
short intracortical inhibition, reduced long intracortical inhibi-
tion, and loss of GABA in the motor cortex with magnetic
resonance spectroscopy. Loss of cortical inhibition in motor
cortex can give rise to dystonic-like movements in primates as
has been shown with local application of bicuculline. Surround
inhibition is a function of the normal motor system. Leocani et
al. evaluated corticospinal excitability of both hemispheres dur-
ing a choice auditory reaction time task for extension of either
left or right thumb. Transcranial magnetic stimulation (TMS)
induced motor evoked potentials (MEPs) simultaneously in the
extensor pollicis brevis muscles bilaterally. MEP amplitudes on
the side of movement increased progressively in the 80120
msec before EMG onset, while the resting side showed inhibi-
tion. This has been extended by Sohn et al. who showed inhi-
bition of the MEP in the abductor digiti minimi muscle with
movement of the flexor digitorum sublimis in the same hand.
Liepert et al. showed an increase in intracortical inhibition in a
hand muscle after practicing a task where that muscle was to be
kept relaxed. The basal ganglia are likely to be the site of
genesis of dystonia and they are appropriately organized to aid
in surround inhibition. Bu tefisch et al. have shown that task-
dependent modulation of inhibition within the motor cortex is
impaired in dystonia using an experimental design similar to
that of Liepert et al. Sohn et al. have shown defective inhibition
in dystonia of the surround muscle with a finger movement.
Learning how to influence surround inhibition may be helpful
in symptomatic treatment.
Sensory Deficits in Dystonia and Their Significance
R. Kaji and N. Murase
Department of Neurology, Tokushima University Hospital,
Tokushima, Japan
Sensory trick is a characteristic feature of dystonia. Dystonic
contractions in writers cramp were reproduced by stimulating
group Ia afferents by high-frequency vibration (tonic vibration
reflex or TVR) and were abolished by blocking them with
diluted lidocaine (muscle afferent block). These findings sug-
gest an abnormal link between sensory input and motor output
in dystonia. Recently marked disorganization sensory represen-
tation of the digits in primary somatosensory cortex was found
in an animal model and patients with hand dystonia. Indeed,
abnormal hand representation in the somatosensory cortex dis-
turbs normal motor-sensory integration in writing; if extrane-
ous sensory input is fed back for subsequent movement, this
would set up a vicious cycle, causing further delapidation of
motor control. To explore this sensorimotor link, Murase et al.
1117
studied the attenuation (gating) of median somatosensory
evoked potentials (SEPs) before and during hand movements in
patients with writers cramp, and found the lack of normal
gating before movements. This indicates a specific abnormality
in utilizing sensory input in preparation for a movement. We
subsequently found the lack of normal gating of P40 of tibial
SEPs in patients with leg dystonia. In normal subjects, these
SEP components are gated because the input channels open for
the limb prior to the movement. Dystonia patients lack this
process specifically for the affected limb, thus interfering with
the sensory feedback control for the execution of the motor
program. Recent animal and human studies suggest that basal
ganglia play an important role in gating sensory inputs for
guiding movements. One of the main hypotheses for the func-
tion of the basal ganglia is to control or select automatic move-
ments after learning. In fact, a recent human study showed
activation of the pallidum after learning a motor task, and it was
argued that the basal ganglia act as a flexible system for learn-
ing the association of sensory cues and movements. If this
flexibility in associating sensory input and motor output is lost
by, for instance, repetitious execution of a learned motor act
such as writing, a fixed input-output mismatch may be the
consequence. Thus dystonia is regarded as a disorder of motor
subroutine in which sensory input and motor output are defined
for controlling frequently used movement.
Focal Hand Dystonia May Result from Aberrant Neuro-
plasticity
N.N. Byl
University of California, San Francisco, California, USA
Focal hand dystonia is a very disabling disorder of move-
ment where co-contractions of the agonist and antagonist lead
to involuntary writhing,or twisting movements that interfere
with the performance of a task. This disorder is especially
disabling for people in occupations that are heavily dependent
on repetitive fine motor use of the hands. There has been in-
creasing attention to the rise in repetitive strain injuries among
computer users and musicians. Some of these individuals later
develop focal hand dystonia. In the last 20 years, it has become
clear that the central nervous system is plastic. It can be modi-
fied by maturation, development and attended repetitive re-
warded behaviors. In 1993 we proposed that one possible origin
of focal hand dystonia was abnormal learning. We proposed
that excessive, attended, stereotypical, near simultaneous hand
movements could degrade the somatosensory representation of
the hand, disrupt the sensorimotor feedback loop and lead to
uncontrollable abnormal movements most specifically while
performing a target task. We created a nonhuman primate
model to generate support for this hypothesis and have since
been trying to implement our findings in the clinic. With time,
while focal hand dystonia is still considered idiopathic, there is
increasing evidence that in some individuals, the condition rep-
resent a case of aberrant learning. In this model, there is no
lesion, but rather negative neural adaptation. The patient is in
the best position to re-educate the nervous system and restore
normal motor control. The purpose of this presentation is to
review the principles of neuroplasticity, relate these principles
to the characteristics of focal hand dystonia, review the evi-
dence that adult onset focal hand dystonia may represent a state
of aberrant learning and integrate the principles of neuroplas-
ticity into a foundation of effective treatment.
Movement Disorders, Vol. 17, No. 5, 2002
1118 4th INTERNATIONAL DYSTONIA SYMPOSIUM
Basal Ganglia Neuronal Discharge in Primary and Second-
ary Dystonia
M.K. Sanghera, W. Ondo, J. Jankovic, R.G. Grossman
Baylor College of Medicine, Houston, Texas, USA
Pallidotomy (PAL) ameliorates levodopa-induced dyskine-
sias of Parkinsons disease (PD) and primary (1) dystonia
(DYS) caused by a mutation of the DYT1 (TOR1A) gene. PAL
is less effective in improving secondary (2) DYS associated
with lesions of the basal ganglia. We have examined putamen
(Put), globus pallidus externa (GPe) and the globus pallidus
interna (GPi) neurons in patients with 1 or 2 DYS (n 15),
and PD (n 78) to determine if there were differences in the
neuronal discharge rate and pattern between 1) awake and anes-
thetized DYS and PD patients; 2) 1 and 2 DYS; 3) DYS
patients who benefited and those who did not benefit from
PAL; and 4) DYS and PD patients. Pallidotomy was performed
on 4 awake DYS and 72 awake PD patients, and on 11 anes-
thetized DYS and 6 anesthetized PD patients. The ages of DYS
patients ranged from 951 years and those of PD patients
ranged from 3978 years. Outcome for PAL was scored on a
global outcome score (GOS): 10 most beneficial; 0 no
benefit or worsening of dystonic symptoms. Our data indicate
that 1) general inhalation anesthesia with desflurane depressed
the discharge rate of GPe and GPi neurons and increased the
irregularity of the discharge pattern in DYS and PD patients; 2)
the mean discharge rate of Put neurons was low in both awake
and anesthetized DYS and PD patients; 3) the mean discharge
rate of both GPe and GPi was lower in DYS patients than in PD
patients in both awake and anesthetized conditions; 4) in DYS
patients, the mean discharge rate of GPe and GPi neurons were
similar, whereas the PD patients, the mean discharge rate of
GPe neurons was lower than the discharge rate of GPi neurons;
5) there was no correlation between the discharge rate or dis-
charge pattern of neurons in patients whose DYS was amelio-
rated by PAL and those who did not benefit from the proce-
dure; 6) there was no significant quantitative differences in the
rate or pattern of discharge of neurons in patients with DYS of
different etiology; and 7) PAL was most effective in patients
with 1 genetic DYS (mean GOS SD 8.1 3.8) and
idiopathic DYS (mean GOS SD 3.5 1.0). Unlike pallidal
neurons in PD patients which have been classified either as
pausers or bursters pallidal neurons in DYS patients dis-
played four distinct discharge patterns: GPe-irregular (52%),
regular (24%), bursting (19%) and clustering (5%); and for
GPi-irregular (61%), regular (14%), bursting (6%) and cluster-
ing (20%). The GPi discharge rate in awake DYS was one third
of that in awake PD. Dopamine agonists depress the firing of
GPi neurons and it is possible that during dopa-dyskinesia, GPi
discharge is depressed to the level seen in DYS. It is unclear
why ablating the GPi should relieve DYS. The disruption of
abnormal firing patterns, rather than changes in frequency, may
produce the beneficial effects of PAL.
Distribution of Impairment of Cortical Inhibitory Mecha-
nisms in Focal Dystonia: A Study of Silent Period Evoked
by Transcranial Magnetic Stimulation
R. Cakmur, B. Donmez, F. Uzunel, H. Aydin, S. Kesken
Department of Neurology, Dokuz Eylul University Medical
School, SSK Tepecik Hospital, Izmir, Turkey
Movement Disorders, Vol. 17, No. 5, 2002
Transcranial magnetic stimulation (TMS) has proved a use-
ful tool to study the pathophysiology of a number of disorders
including dystonia. Shortening of cortical silent period (CSP)
evoked by TMS has been reported in both cranial dystonia and
cervical dystonia. In these studies, evaluation of CSP has fo-
cussed mainly on the affected muscles. Since it has been dem-
onstrated that abnormality in central mechanisms is probably
more generalized than is apparent in focal dystonia, we studied
CSP in cranial, cervical and hand muscles in patients with focal
dystonia. High-intensity magnetic stimulation was delivered
with a round coil centered at the vertex during maximal con-
traction of muscles in 30 patients with focal dystonia (14 es-
sential blepharospasm and 16 cervical dystonia) and 20 normal
controls. Our preliminary results showed that CSP is signifi-
cantly shorter in affected muscles in both patient groups. More-
over there was also shortening of CSP in cranial muscles of
patients with cervical dystonia. This finding supports previous
electrophysiological studies showing hyperexcitable blink re-
flexes in patients with cervical dystonia. CSP was normal in
hand muscles in both groups. These results indicate an impair-
ment of the mechanisms of cortical inhibitory control in focal
dystonia, which is more widespread in cervical dystonia.
Lasting Suppression of the Premotor Cortical Overactivity
in Arm Dystonia by Repetitive Transcranial Magnetic
Stimulation: A Clinical and PET Activation Study. Prelimi-
nary Data
S.R. Filipovic, H.R. Siebner, J.B. Rowe, C. Cordivari, W. Ger-
schlager, J.C. Rothwell, R.S.J. Frackowiak, K.P. Bhatia.
Institute of Neurology, Queen Square, London, United King-
dom
Background: In previous functional imaging studies, patients
with arm dystonia demonstrated increased movement-related
activity in the rostral premotor and prefrontal cortical areas
compared with healthy subjects. Separately, it has been shown
that low-frequency repetitive transcranial magnetic stimulation
(rTMS) is capable of inducing a lasting inhibition of the tar-
geted cortical area. Objective: We studied the clinical and re-
gional cerebral blood flow (rCBF) effects of rTMS applied over
the premotor cortex in patients with arm dystonia. Methods:
This is a single-blinded placebo-controlled crossover study.
Intervention (real rTMS) was 30 minutes of the sub-threshold
slow-frequency rTMS (intensity: 90% of the resting motor
threshold; rate: 1Hz) over the left premotor cortex. Placebo
(sham rTMS) was done using the same parameters but with
the sham coil (i.e. no magnetic field induction but with the
same sound). The order of real and sham TMS was coun-
terbalanced across subjects, and sessions were separated by at
least 7 days. Normalised rCBF was measured using H2O15 PET
immediately after the end of the each rTMS session. Each
scanning session included three scans during paced freely se-
lected finger movements of the right hand (active) alternating
with rest scans (rest). Images were processed and analysed
using SPM99. The analysis used a general linear model includ-
ing covariates for disease Group (patient vs. control), Task
(active vs. rest) and rTMS (real vs. sham). Two age- and sex-
matched groups of subjects were formed, idiopathic arm dys-
tonia group, and control group of healthy volunteers. We pre-
sent the results on the first 6 patients and 5 controls. Results:
The contrast of movement selection (active) versus rest re-
vealed significant activation throughout the motor system, in-
 4th INTERNATIONAL DYSTONIA SYMPOSIUM
cluding motor and premotor areas, cerebellum and basal gan-
glia. Moreover, real but not sham rTMS significantly reduced
rCBF in the left premotor region (14, 2, +62), in both active
and rest conditions. However, the significant (P < 0.05, cor-
rected) Group rTMS interaction was found: the effect of
rTMS in the premotor cortex (22, 0, +54) was significantly
greater in the dystonic patients than controls. In addition, in
both groups, there were several remote effects of rTMS includ-
ing reduced rCBF in the left medial parietal cortex (10, 60,
+56) and left anterior temporal lobe (30, 6, 18). Conclu- voice breaks within patients with adductor and abductor spas-
sions: The preliminary results we obtained so far suggest that it
is possible, by the means of the slow rTMS, to reduce the
metabolic overactivity of the premotor cortex in dystonic pa-
tients. These data also prove that rTMS is able to induce sus-
tainable plastic changes in central nervous system functional
networks. Although the time-course of recovery from the rTMS
remains uncertain, this virtue of rTMS open an interesting per-
spective for possible therapeutic application of rTMS in dys-
tonia and other movement disorders.
The Role of Afferent Feedback in Symptom Generation in
Spasmodic Dysphonia
C.L. Ludlow, E.A. Mann, M. Allamarvdasht, E. Andersson, C.
Poletto
Laryngeal and Speech Section, National Institute of Neurologi-
cal Disorders and Stroke, National Institutes of Health,
Bethesda, Maryland, USA
Background: In spasmodic dysphonia, involuntary spas-
modic bursts in the laryngeal muscles disrupt vocal fold vibra-
tion producing voice breaks, the primary symptom of the dis-
order. Previously, we have found that electrical stimulation of
laryngeal afferents will produce adductor (thyroarytenoid)
muscle responses in awake humans. Adductor muscle re-
sponses include an early ipsilateral thyroarytenoid muscle re-
sponse, R1, and a late R2 muscle response. When pairs of
electrical stimuli were presented to afferents in the superior
laryngeal nerve, R2 responses to the second stimulus of a pair,
the conditioned stimulus, are reduced in frequency in awake
humans. Previous studies in both adductor spasmodic dyspho-
nia and abductor spasmodic dysphonia have demonstrated that
the suppression of conditioned responses was significantly re-
duced in both patient groups. This led to the hypothesis that
afferent feedback to the brain stem might have a role in the
generation of spasmodic bursts in the laryngeal muscles in
adductor and abductor spasmodic dysphonia. Objective: To de-
termine whether a temporary chemical block of the laryngeal
sensory nerves on both sides of the larynx alters the frequency
and duration of voice breaks in spasmodic dysphonia. Methods:
Speech was recorded on two sets of 10 sentences prior to the
procedure. Laryngeal sensory thresholds in mm of Hg were
measured using 100 msec air puff stimuli to the epiglottis and
the mucosa covering the arytenoid cartilages. Two to 3 ml of
2% lidocaine was injected in the region of the superior laryn-
geal nerve above the thyrohyoid membrane on each side. Sub-
jects were questioned regarding the onset of the sensation of
globus in the laryngeal area. Once this occurred, usually within
10 minutes post injection, the same 20 sentences were pre-
sented for repetition. Air puff sensory threshold testing was
then repeated to confirm a block of the laryngeal afferents.
Results: Clinically significant reductions in voice breaks fol-
lowing the bilateral sensory block were noted in all participants
1119
at the time of testing to date. The patients also reported that
speech was less effortful after the block. Continuous abnor-
malities in voice quality, such as harshness or breathiness, how-
ever, were less affected. Acoustic analyses are being conducted
from sentences coded to prevent knowledge of condition (pre-
or post-block). Measures include the frequency and duration of
both adductor and abductor voice breaks and sentence duration
in sentences before and after block. Conclusions: Quantitative
data will be presented on the results of the afferent block on
modic dysphonia. The data suggest an essential role of sensory
feedback in the generation of laryngeal muscle spasms in the
disorder. It is unclear whether continuous voice quality abnor-
malities represent an independent abnormality or a compensa-
tory strategy used by patients to cope with their disorder. The
study supports the importance of sensory feedback in symptom
generation for adductor and abductor spasmodic dysphonia.
Secondary Cervical Dystonia Associated with Structural
Lesions of the Central Nervous System
M.S. LeDoux and K.A. Brady
Department of Neurology, University of Tennessee Health Sci-
ence Center, Memphis, Tennessee, USA
Background: Cervical dystonia is the most common focal
dystonia, the majority of cases are idiopathic, and only a small
percentage of patients have a family history of dystonia or other
movement disorders. Pathophysiological mechanisms opera-
tive in solely or predominantly appendicular dystonias such as
writers cramp and Oppenheims dystonia, respectively, may
not be directly applicable to axial dystonias. The localization of
structural lesions of the central nervous system associated with
secondary cervical dystonia may provide some insight into the
neural structures potentially involved in primary cervical dys-
tonia. Objective: To test the hypothesis that structural lesions of
the central nervous system associated with cervical dystonia
more commonly involve the cerebellum and its primary affer-
ent pathways than basal ganglia structures. Methods: The Na-
tional Library of Medicine Gateway (from 1960) and a clinical
database maintained by the senior author (from 1999) were
searched for cases of secondary cervical dystonia associated
with structural lesions of the central nervous system. Search
terms included one or more of the following: dystonia, torti-
collis, cervical, secondary, and symptomatic. Lesion localiza-
tion and type, patient age, patient gender, head position, occur-
rence of sensory tricks, and associated neurological findings
were tabulated for each case. Results: The senior authors da-
tabase contained four cases of secondary cervical dystonia as-
sociated with structural lesions of the central nervous system:
pontine ischemic infarct, posterior thalamic ischemic infarct,
cerebellopontine angle arachnoid cyst, and pontine hemor-
rhagic stroke. A total of 21 additional cases were identified in
the published literature since 1960. Structural lesions associ-
ated with cervical dystonia were most commonly localized to
the brainstem and cerebellum. The remaining cases were
equally divided between the cervical spinal cord and basal gan-
glia. Although inconsistent, head rotation tended to be contra-
lateral to lesion localization. Additional neurological abnor-
malities were present in the majority of patients with secondary
cervical dystonia. Some patients with secondary cervical dys-
tonia exhibited sensory tricks. Many patients with secondary
cervical dystonia responded to treatments such as botulinum
Movement Disorders, Vol. 17, No. 5, 2002
1120 4th INTERNATIONAL DYSTONIA SYMPOSIUM
toxin injections and anticholinergics that are used for patients
with primary cervical dystonia. Conclusions: The relative pau-
city of basal ganglia pathology and concentration of lesions in
the brainstem, cerebellum, and cervical spinal cord in patients
with secondary cervical dystonia suggests that dysfunction of
cerebellar afferent pathways may be important to the patho-
physiology of primary cervical dystonia.
Cognitive Executive Function in Idiopathic Dystonia
M. Jahanshahi,1 J. Rowe,2 R. Fuller1
1
Department of Clinical Neurology, Institute of Neurology, The
National Hospital for Neurology and Neurosurgery, London;
2
Department of Clinical Psychology, East London and The City
Mental Health Trust, Homerton Hospital, London, United
Kingdom
Dystonia is a movement disorder considered to be due to
basal ganglia dysfunction and imaging studies have revealed
functional abnormalities in fronto-striatal areas in the disorder.
Objective: To investigate the functional significance of the
frontal hyperactivity demonstrated in dystonia in imaging stud-
ies by examining executive function and working memory in
which the prefrontal cortex is known to be involved. Methods:
We assessed 12 patients with idiopathic Dystonia and 12 age-
matched normal controls. All subjects completed tests of first
letter, category and alternating category word fluency, the Wis-
consin Card Sorting test, the Stroop Colour Word Intereference
test, the missing digit test, a test requiring generation of self-
ordered random number sequences, the paced serial addition
test, a test of Conditional Associative Learning, and finger
tapping and peg insertion under unimanual, bimanual and dual
task conditions. Results: Although the patients had lower scores
than the controls on all tests, after co-varying out group differ-
ences in depression and premorbid IQ, the patients did not
significantly differ from the controls on any of the measures of
executive function used other than extent of decline in tapping
with the right hand under dual task conditions when simulta-
neously inserting pegs with the left hand. Conclusion: These
results suggest that unlike other movement disorders associated
with fronto-striatal dysfunction such as Parkinsons disease and
Huntingtons disease, Dystonia is not associated with deficits
on tests of executive function and can be considered to be
primarily a motor disorder.
II. OPPENHEIMS DYSTONIA
Biochemistry of Oppenheims Dystonia
S.J. Augood
Neurology Research, Massachusetts General Hospital and
Harvard Medical School, Charlestown, Massachusetts, USA
Background: In 1911 Herman Oppenheim coined the term
dystonia to describe a unique cramping sickness observed in receptors (post-synaptic). We report on 3 other genetically-
children and teenagers. The combination of hypotonia and
hypertonia in these children resulted in their muscles fluctuat-
ing between involuntary contraction and tonic spasms, resulting
Movement Disorders, Vol. 17, No. 5, 2002
in twisted postures. Despite the severity of these muscle fluc-
tuations, Oppenheim noted that there was no muscle atrophy,
muscle weakness or any alteration in electrical excitability in
any of these patients that would account for their unusual motor
symptoms. Further, the patients appeared cognitively intact
suggesting that their symptoms were not due to hysteria as
previously suggested. Although these unusual twisted postures
had been described previously, it was Oppenheim who first
hypothesized that these symptoms had an organic basis. Op-
penheims dystonia, or dystonia muscularum deformans, is
one of the primary genetic dystonias. Onset of symptoms is
usually before the age of 28 years and manifests initially in
distal limbs and later progresses to affect multiple body parts.
This disorder is most prevalent amongst Ashkenazi Jews and is
now known to be caused by deletions within the protein coding
region of the TOR1A (DYT1) gene. The heterozygous GAG
deletion in TOR1A has low penetrance, approximately only
30% of people with the mutation develop clinical symptoms,
which initially led to the hypothesis of an autosomal recessive
mode of inheritance. The TOR1A gene encodes a novel protein
termed torsinA whose function is currently unknown, although
sequence homology studies have revealed a similarity with the
AAA+ family of ATPases which perform chaperone-like func-
tions and assist in protein trafficking and membrane fusion.
Despite the identification of deletions within the TOR1A gene
in Oppenheims dystonia, the etiology of this disease still re-
mains elusive and effective therapies are limited. During the
last two decades several biochemical studies have been carried
out in patients with childhood-onset dystonia muscularum de-
formans, although no consistent biochemical abnormality has
been identified. Further, no gross neuropathological abnormal-
ity is observed postmortem in primary childhood-onset gener-
alized dystonia, in contrast to other degenerative disorders in-
cluding Wilsons disease and Parkinsons Disease, where dys-
tonia is a prominent symptom, further complicating the search
for the etiology of this debilitating disorder. Several other
forms of dystonia are now known to be caused by a deficit in
striatal dopamine (DA). For example, point mutations within
the tyrosine hydroxylase (TH) gene, the rate-limiting enzyme in
the DA synthesis pathway, within the GTP cyclohydrolase
gene, and within the DA D2 receptor gene result in a dystonic
phenotype in man. Administration of pharmacological agents
that block DA D2 receptors in vivo can similarly result in a
dystonic phenotype as can mechanical or ischemic lesions of
the striatum. Further, torsinA mRNA and protein are highly
expressed within the nigro-striatal pathway in the post-mortem
human brain. Consequently, it has been hypothesized that
DYT1 (Oppenheims) dystonia is associated with an imbalance
in DA signaling in the developing human brain. Objective: To
examine comprehensively markers of DA signaling within the
striatum of three genotypically confirmed DYT1 dystonia
brains. Methods: Biochemical indices of striatal DA transmis-
sion were examined by measuring the tissue content of DA and
its metabolites DOPAC and homovanillic acid (HVA), whereas
markers of DA transmission were examined by quantitative
autoradiography using tritiated ligands for the DA (mazindol)
and vesicular (dihydrotetrabenazine DHTB) transporters (pre-
synaptic) and DA D1 (SCH-23390) and DA D2 (YM-09151-2)
confirmed DYT1 dystonia cases. Results: We found a 23%
reduction in striatal DA content and a 48% increase in dopa-C
content in DYT1 dystonia. Although neither of the changes
 4th INTERNATIONAL DYSTONIA SYMPOSIUM
alone was statistically significant, these absolute values trans-
lated into a significant increase (+71%) in striatal dopa-C/DA
ratio in DYT1 dystonia. These biochemical indices of DA
transmission are indicative of an intact dopaminergic nigro-
striatal system, although the increased dopa-C/DA and HVA/
DA ratios are consistent with an increase in DA turnover in the
DYT1 striatum compared to controls. Biochemical evaluation
of 2 other cases of DYT1 dystonia exist in the literature, and in
both cases striatal DA and HVA tissue content was found to be
similar to controls, however, tissue DOPAC content was not
reported. Examination of markers of post-synaptic DA trans-
mission revealed a similar picture to the biochemical data. Do-
pamine D1-like and D2-like binding were decreased in the
DYT1 striata, although in neither case did the mean reduction
achieve significance. In particular, a 29% reduction in D1-like
and a 40% reduction in D2-like binding were measured. Thus,
the biochemical data coupled with the receptor autoradiography
are highly suggestive of an imbalance in DA signaling within
the DYT1 striatum, in particular an increase in DA turnover.
Conclusions: These data are consistent with the hypothesis that
in DYT1 (Oppenheims) dystonia mutant torsinA may impact,
preferentially, on the dopamine system in vivo to perturb stria-
tal signaling. Thus, our findings will be presented and dis-
cussed in light of the recent anatomical data localizing torsinA
immunostaining to symmetrical, putative dopaminergic, syn-
apses in the primate striatum.
Cell Biological and Biochemical Analysis of Torsin A
B. Lauring
Department of Pathology, Taub Institute for Research on Alz-
heimers, Disease and the Aging Brain, College of Physicians
& Surgeons, Columbia University, New York, New York, USA
Torsin dystonia is an autosomal dominant primary dystonia
caused by a one amino acid deletion in the gene encoding
Torsin A, a member of the AAA+ family of ATPases. Torsin A
is a lumenal resident endoplasmic reticulum (ER) protein of
unknown function. Soluble and integral membrane proteins en-
tering the secretory pathway enter the ER through the translo-
con, which is a multiprotein machine that co-translationally
translocates proteins across the ER membrane. In the ER pro-
teins must fold and oligomerize with their binding partners.
There also exists an elaborate quality control mechanism in the
ER which identifies misfolded or improperly oligomerized pro-
teins and targets them for reverse translocation through the
translocon back into the cytosol where they are degraded by the
ubiquitin-proteasome system. AAA ATPases which function in
a dizzying array of cellular processes are found in many sub-
cellular locations and are structurally divergent. They do how-
ever all share the so-called AAA+ ATPase domain. A common
molecular mechanistic theme among the best studied members
of the family is the that the energy from ATP hydrolysis drives
conformational changes not only in the AAA+ ATPases, but
often in associated substrate proteins as well. In many cases,
these ATPases drive disassembly or unfolding reactions
Loosely defined, many AAA proteins function in protein qual-
ity control reactions In E. coli, the hexameric Clp A protein
unfolds proteins pre-tagged for degradation and feeds them into
the lumen of the barrel shaped Clp P protease for degradation.
Other AAA+ proteins residing in the E. coli plasma membrane
or in mitochondrial membranes effect both the dislocation of
proteins from membranes and, via metalloprotease domains,
1121
the degradation of integral membrane protein substrates. Yet
another AAA+ protein, p97/cdc48p, forms a heteromeric com-
plex that dislocates ubiquitinated substrates from the ER mem-
brane. Based on the data described below and by analogy to the
functions of some of the AAA proteins described above, we
present a working hypothesis for Torsin A function. Overex-
pression of the dystonia associated E Torsin A in cultured
cells induces formation of concentric whorls of endoplasmic
reticulum membrane called karmellae.We established stable
cell lines where expression of human Torsin A (WT, E, or the
presumably ATPase deficient E171Q) is under the control of an
inducible promoter. When the Torsin A is recovered from cell
lysates by metal ion affinity chromatography, -[32P] -ATP can
be UV crosslinked to both the WT and E Torsins. As in
mammalian cells, expression of E but not WT Torsin A in-
duced karmellae formation. Furthermore, expression of the pu-
tatively ATPase deficient Torsin A also induced karmellae for-
mation. These results indicate that a novel mutation predicted
to affect Torsin As enzymatic activity gives a cellular pheno-
type similar to that observed by the disease-causing mutation.
Karmellae formation is often induced upon overexpression of
integral membrane proteins such as HMG-CoA reductase or
cytochrome P-450. We also found that Torsin is present in
purified canine pancreatic rough microsomes. In both these
membranes and in the S2 cells Torsin is not an integral mem-
brane protein by either of the two operational definitions: 1)
resistance to alkaline extraction, and 2) recovery in the deter-
gent phase after extraction with Triton X-114. To our knowl-
edge, Torsin is the first non-integral protein to be associated
with karmellae formation. Sub-fractionation of the purified ER
membranes showed that while a fraction of Torsin is soluble in
the ER lumen, another fraction is associated with the translo-
con. We also show that these Torsin-containing translocon
complexes isolated from mammalian ER membranes are ca-
pable of unfolding cholera toxin, a protein that normally un-
folds in the ER, in an ATP-dependent manner. Given that dom-
inant mutations in Torsin A cause a phenotype usually pro-
duced by accumulation of integral membrane proteins, the
translocon association of Torsin , and the potential ability to
unfold substrates, we hypothesize that Torsin A is involved in
removal of proteins, particularly integral membrane proteins,
from the ER. We further speculate that Torsin A is an unfoldase
that directs ERAD substrates into the translocon as part of the
ERAD (ER-associated degradation) response.
Distribution of Torsin A in the Developmental and Adult
Rat Brain
S.R. Oberlin,1 M. Konakova,2 S.M. Pulst,2,3 M-F. Chesselet4
1
Department of Neurology, University of California-Los Ange-
les, Los Angeles, California; 2Rose Moss Laboratory for Par-
kinson and Neurodegenerative Diseases, CSMC Burns and
Allen Research Institute; 3Division of Neurology, Cedars Sinai
Medical Center, UCLA School of Medicine, Los Angeles, Cali-
fornia; 4Department of Neurology and Brain Research Insti-
tute, University of California-Los Angles, Los Angeles, Cali-
fornia, USA
Dystonia is a neurological movement disorder characterized
by sustained muscle contractions causing abnormal posture and
repetitive, twisting motions. Early-onset dystonia is thought to
be a developmental disorder of the basal ganglia, however,
there is currently no evidence of neurodegeneration. This most
Movement Disorders, Vol. 17, No. 5, 2002
1122 4th INTERNATIONAL DYSTONIA SYMPOSIUM
common form of primary dystonia has been linked to a 3 base-
pair GAG deletion in the DYT1, which encodes the novel
protein Torsin A. In this study we identify the distribution of
Torsin A in the developmental and adult rat brain using two
specific antibodies generated against Torsin A, TR1 and TR2.
We find that there is an overall increase in the level of expres-
sion of Torsin A during development. Expression is specific to
the cytoplasm of neuronal cell bodies and fibrous processes
with some indication of staining within the nucleolus. At P1
expression is confined to specific regions including the brain-
stem, pontine nucleus, specific thalamic nuclei, and the stria-
tum. At P7 the distribution of Torsin A expands incorporating
the lateral globus pallidus, medial globus pallidus, subthalamic
nucleus and specific areas of the superior colliculus. By P14
Torsin A is ubiquitously expressed throughout most regions of
the brain. The most significant change in the level of expression
was observed in the cholinergic interneurons within the stria-
tum. Beginning at P7 Torsin A expression in cholinergic inter-
neurons increases compared to the level of expression in me-
dium spiny neurons. This change in the level of intensity peaks
at P14, continues through P21, and declines to adult levels by
P28. This pattern of intensity may indicate that Torsin A is
important in regulating the development of cholinergic inter-
neurons and may suggest a potential mechanism explaining the
effectiveness of anti-cholinergic drugs in the treatment of pa-
tients with early-onset dystonia.
Animal Models
W. Dauer
Columbia Presybterian, New York, New York, USA
Primary dystonia research has been hampered by the lack of
an etiological specific animal model of the disease. DYT1 (Op-
penheims) dystonia, the most common form of early-onset
primary dystonia, is an autosomal dominant disorder caused by
an in-frame GAG deletion (glutamic acid) in the TOR1A gene.
The TOR1A gene encodes torsinA, a AAA protein of unknown
function that resides in the ER. We have generated torsinA
knock out mice and find that while these animals are born with
normal Mendelian frequency, they fail to feed and die within 24
hours of birth. TorsinA knock out pups appear grossly normal,
and histological analysis of the brain and other organs is unre-
markable. No abnormalities have been observed in a number of
defined neuronal populations, including dopaminergic neurons,
and cranial, olfactory and sensory neurons. Further, torsinA
knock out primary cortical cultures appear grossly normal, and
do not display a deficient ER stress response. We have also
used gene targeting to generate a pair of torsinA knock in mice
that lack either the disease-associated glutamic acid deletion
(E1) or a downstream glutamic acid (E2). Both of these muta-
tions cause torsinA to acquire an abnormal punctate pattern of
immunostraining in transient transfection studies. Mice homo-
zygous for the E2 mutation born with normal Mendelian fre-
quency, and are viable, fertile and indistinguishable from their
wild type littermates. While these mice do not display any
obvious abnormal involuntary movements, they are signifi-
cantly impaired in rotarod performance. The dopaminergic sys-
tem of these mice appears normal, as assessed by their motor
response to GBR-12909 (blocks dopamine transporter), quan-
titative autoradiography for D1 and D2, and dopamine trans-
porter immunostaining. The morphological abnormalities ob-
Movement Disorders, Vol. 17, No. 5, 2002
served when E2 torsinA is transiently expressed in vitro are not
observed in the E2 knock in mice. A comparison of the phe-
notypes of the knock out and knock in mice suggest that the
DYT1 mutation does not obliterate torsinA function. Further,
the fact that the E2 knock in mice display an abnormal behav-
ioral phenotype in the absence of morphological abnormalities
of ER suggests that these morphological changes are not re-
quired for mutant torsinA to produce motor dysfunction. Fur-
ther analysis of these torsinA mutant mice will help to elucidate
the function of torsinA and how the DYT1 mutation disrupts
this function to lead to abnormal motor behavior.
A Transgenic Mouse Model for DYT1 Dystonia
P. Shashidharan, M.F. Brin, P. Gujjari, D. Sandu, and C.W.
Olanow
Department of Neurology, Mount Sinai School of Medicine,
New York, New York, USA
Childhood-onset torsion dystonia is a progressive disabling
disorder of motor control, characterized by abnormal, involun-
tary muscle contractions. A three base pair (GAG) deletion in
the coding region of DYT1 gene has been identified as a cause
for this disorder. The DYT1 gene encodes for a protein called
torsinA, which is expressed in brain and many peripheral tis-
sues. In brain, the expression of torsinA is restricted to neurons.
Neither the normal cellular function of torsinA nor how its
dysfunction leads to dystonia is known. To determine the effect
torsinA mutation on brain function, we have developed trans-
genic mice expressing human mutant torsinA. Genotype of
mice was determined by PCR amplification and restriction
analysis of genomic DNA from tail biopsies. The transgenic
mice were able to feed normally and their weight gains were
comparable to that of wild type controls. The mice were able to
reach sexual maturity and produce normal sized litters. Some
but not all of the transgenic mice exhibited abnormal circling
and hyperkinetic movements. Approximately 35% of trans-
genic mice developed these abnormal hyperkinetic and circling
behaviors. The pattern of abnormal motor activity developed in
mice between 3 and 10 weeks of life and remained for the rest
of their lives. As not all-transgenic mice show this abnormal
phenotype, other secondary factors may be necessary for the
precipitation of the symptoms, which is presently not known.
Interestingly the percentage of mice exhibiting the abnormal
symptoms is comparable to the human condition. In humans,
30 to 40% of the mutant gene carriers develops abnormal motor
function. This transgenic mouse model will give us an oppor-
tunity to address some of these questions and may provide
clues to the pathophysiology of childhood onset dystonia.
[Note: This work was supported by the National Institutes of
Health (NINDS NS43038) and by the Bachmann-Strauss Dys-
tonia and Parkinson Foundation, New York.]
Dominant TorsinA Mutations in Cellular Systems
C.A. OFarrell,1 D. Hernandez,1 A.B. Singleton,1,2 M.R. Cookson1
1
Mayo Clinic Jacksonville, Jacksonville, Florida; 2National In-
stitute on Aging, Bethesda, Maryland, USA
Dominant mutations in the gene encoding for the novel pro-
tein torsinA are associated with a familial form of dystonia. To
date, two apparently dominant mutations have been described,
 4th INTERNATIONAL DYSTONIA SYMPOSIUM
both in-frame deletions in the C-terminal portion of the protein.
The function of torsinA has not been identified. However, re-
sults from several laboratories suggest that at least one of the
mutant forms may have a propensity to form intracellular in-
clusions when transiently expressed at high levels in cultured
cells. It is not clear how the mutation exerts a dominant effect
in the presence of wild type protein. There are three formal
possibilities for possible effects of the mutation on protein
function. Firstly, mutant torsinA may exert a toxic gain of
function. Secondly, the expression of mutant torsinA may de-
crease wild type function, thus acting as a dominant negative.
Finally, it is possible that dystonia occurs because two fully
functional copies of the gene are required (haploinsufficiency).
To distinguish between these possibilities will require several
approaches. In the present study we have used cell culture
models to dissect the effect of expression of mutant torsinA on
the localization of wild type protein. We have been able to
reproduce the previous reports of mislocalization of E303-
torsinA in cytoplasmic inclusions in neuronal or non-neuronal
cell lines. Wild-type protein expressed at similar levels did not
produce such aggregates. However, we have not seen such
inclusions formed with a more recently reported 18 base pair
(F323-Y328) deletion, raising the possibility that the forma-
tion of these intracellular inclusions is specific to E303. Simi-
lar experiments in virally transduced post-natal mouse brain
primary neuronal cultures will be presented. Preliminary im-
munoprecipitation data suggests that wild type torsinA and ? ?
303 torsin A interact. However, steady state levels of torsinA
protein do not appear to be affected by the level of mutant
protein present. These model systems may be used to address
the hypothesis that torsinA exert their deleterious effects by
affecting wild type protein localization or levels.
In Vivo Suppression of Protein Aggregation by a C. elegans
Torsin Homologue
G.A. Caldwell, E.G. Sexton, S. Cao, J.P. Bevel, K.A. Caldwell
University of Alabama, Department of Biological Sciences,
Tuscaloosa, Alabama, USA
Torsion dystonia is an autosomal dominant movement dis-
order characterized by involuntary, repetitive muscle contrac-
tions and twisted postures. The most severe early-onset form of
dystonia has been linked to mutation in the human TOR1A
(DYT-1) gene encoding a protein termed torsinA. While caus-
ative genetic alterations have been identified, the function of
torsinA and molecular mechanism underlying dystonia remain
unknown. Phylogenetic analysis of the torsin protein family
indicates these proteins share distant sequence similarity with
the large and diverse family of AAA+/HSP/Clp-ATPase pro-
teins. We have established the nematode, Caenorhabditis el-
egans, as a model system for examining torsin activity. C.
elegans has 959 somatic cells, including a nervous system con-
sisting of only 302 neurons (vs. >100 billion in the human
brain). However, this simple nematode is capable of compli-
cated behaviors, many of which are directly associated with
specific neurotransmitters (dopamine, serotonin, acetylcholine)
and neuromuscular responsiveness. The ability to rapidly per-
turb protein function genetically, in the context of an intact and
visually transparent animal with defined neuronal processes, is
highly advantageous for analyses linking genetic abnormality
to anatomical structure and cellular function. Aberrant protein
1123
deposition is associated with diverse neurological disorders in-
cluding neurodegenerative diseases caused by polyglutamine
expansion such as spinocerebellar ataxias and Huntingtons
disease. Immunocytochemical analyses of inclusions termed
Lewy bodies, a clinical characteristic of post-mortem brains
from patients with Parkinsons disease, revealed an intense
reactivity for torsinA. Among movement disorders, dystonia
remains poorly understood due to an absence of neuronal de-
generation, thus rendering it difficult to pathologically define.
Progress toward delineating torsin expression and localization
has been reported but intracellular activities have not been elu-
cidated. We exploited the experimental advantages of C. el-
egans to investigate torsin function using an in vivo assay for
examining states of intracellular protein aggregation. A nema-
tode torsin homologue, TOR-2, localized to cellular sites of
polyglutamine repeat-induced fluorescent protein aggregation
and dramatically suppressed the formation of inclusions in
transgenic animals. Suppressive effects of torsin overexpres-
sion persisted as animals aged, whereas a mutant torsin was
incapable of ameliorating aggregate formation. Antibody stain-
ing of transgenic animals using antisera specific to TOR-2 in-
dicated this protein was highly localized to sites of protein
aggregation, wherein it appeared to form a complex with the
aggregated protein, as determined by co-immunoprecipitation.
The intracellular response to protein misfolding represents an
undefined biological mechanism with significant consequences
for therapeutic intervention; implication of torsins in this pro-
cess provides a context for better understanding dystonia and
its relation to other disease mechanisms.
TorsinA in PC12 Cells: Localization in the Endoplasmic
Reticulum and Response to Stress
X. Breakefield,1 J. Hewett,1 P. Ziefer,1 D. Bergeron,1 T. Nai-
smith,2 H. Boston,1 D. Slater,1 J. Wilbur,1 D. Schuback,1 C.
Kamm,1 L. Ozelius,3 V. Ramesh,1 P.I. Hanson2
1
Molecular Neurogenetics Unit, Department of Neurology,
Massachusetts General Hospital, and Neuroscience Program,
Harvard Medical School, Boston, Massachusetts; 2Department
of Cell Biology and Physiology, Washington University School
of Medicine, St. Louis, Missouri; 3Department of Molecular
Genetics, Albert Einstein College of Medicine, Bronx, New
York, USA
Most cases of early onset torsion dystonia are caused by loss
of a glutamic acid in the carboxy terminal of torsinA. This
autosomal dominant neurological disorder is characterized by
abnormal movements, believed to originate from neuronal dys-
function in the basal ganglia of the human brain. TorsinA is a
member of the ATPases associated with a variety of cellular
activities (AAA+) superfamily of proteins that mediate chap-
erone functions involved in conformational modeling of pro-
teins, protection from stress, and targeting of proteins to cellu-
lar organelles. In this study, the intracellular distribution and
levels of endogenous torsinA were evaluated in the neuroen-
docrine cell line, rat pheochromocytoma PC12, following dif-
ferentiation and stress. TorsinA, apparent MW 37 kD, co-
fractionates with markers for the microsomal/endoplasmic re-
ticulum (ER) compartment and resides primarily within the ER
lumen. TorsinA-immunoreactivity co-localizes with the lumen-
al ER protein, protein disulfide isomerase (PDI), and the ve-
sicular marker, VAMP (synaptobrevin), extending throughout
Movement Disorders, Vol. 17, No. 5, 2002
1124 4th INTERNATIONAL DYSTONIA SYMPOSIUM
neurites to their endings, with accumulation at varicosities.
Levels of torsinA did not increase notably in response to nerve
growth factor-induced differentiation or heat shock. Among a
number of stress conditions tested, oxidative stress resulted in
a marked increase in both the apparent amount and MW of
torsinA. These studies are consistent with a role for torsinA in
ER-based chaperone functions, with a high sensitivity to oxi-
dative stress. Mutant torsinA may interfere with and/or com-
promise these ER functions, especially in dopaminergic neu-
rons, which have high levels of torsinA and are intrinsically
vulnerable to oxidative stress.
Microarray Analysis of a Cell Culture Model of Early-
Onset Dystonia Linked to Torsin A Mutations
M.J. Baptista,1 C. OFarrell,2 M.R. Cookson1
1
Neurogenetics Laboratory, NIA/National Institutes of Health,
Bethesda, Maryland; 2Neurogenetics Laboratory, Mayo Clinic
Jacksonville, Jacksonville, Florida, USA
Early-onset torsion dystonia is a movement disorder charac-
terized by sustained muscle contractions and abnormal posture.
A deletion in a conserved region of the torsinA gene, resulting
in the loss of a one of a pair of glutamate residues (E302/303),
has been detected in a large number of patients with chromo-
some 9-linked primary dystonia (DYT1). However, mutations
in torsinA are not fully penetrant and some genetic heteroge-
neity has been noted, suggesting that additional genetic fac-
tor(s) may play a role in the development of this disease. The
first aim of the current study was to use a cell culture model of
torsinA over-expression to identify additional genes relevant to
dystonia. There are few clear reports of specific pathology
associated with DYT1 or other forms of dystonia. Therefore,
the second aim of the current study was to identify genes whose
expression is altered by torsinA in the hope of identifying novel
markers of cellular dysfunction caused by the presence of these
mutations. Clonal cell lines over-expressing either wild type
torsinA or the E302/303 mutation were generated by stable
transfection of HEK293 cells with appropriate cDNAs in mam-
malian expression vectors. We measured torsinA expression
using both RT-PCR and protein and identified several clones of
both wt and E302/303 with similar levels of expression. Simi-
lar to previous studies, we noted the presence of ER-derived
intracellular inclusions in E302/303 transfected cells, which
were maintained after selection and serial passage of the cells.
We then used the oligo-based U95A GeneChip (Affymetrix,
Santa Clara, CA) to globally compare the expression levels of
12,500 non-redundant cDNAs and ESTs. The microarray data
will be confirmed by quantitative RT-PCR using SYBR green
as a reporter. It is expected that identification of additional gene
families regulated by over-expression of torsinA, both wild
type and the E302/303 mutation will provide additional in-
formation towards defining a pathway leading to dystonia.
Characterization of Torsin B and Expression in Human
Brain Relative to the Dystonia-Associated Torsin A Protein
C.A. OFarrell,1 P.J. Lockhart,1 S. Lincoln,1 D. Hernandez,2
A.B. Singleton,2 M.R. Cookson2
1
Department of Neuroscience, Mayo Clinic Jacksonville, Jack-
sonville, Florida; 2Laboratory of Neurogenetics, National In-
stitute on Aging, Bethesda, Maryland, USA
Movement Disorders, Vol. 17, No. 5, 2002
Mutations in torsinA, a member of the AAA family of
ATPases, are associated with early onset-dystonia. A closely
related homologue, torsinB, has also been described, although
the significance of this second form is not clear. Here we de-
scribe the cloning of a full-length cDNA for torsinB and dem-
onstrate that in transfected cells it has similar properties to
torsinA. The limited previous studies of torsinB have suggested
that the molecular weight is greater than that of torsinA. We
looked for alternate start sites in torsinB using 5 RACE and
identified two products, which were both sequenced. We were
unable to identify any alternate start sites other than the major
species leading to a predicted 38-kDa protein. Additionally, we
examined mRNA expression of torsinB using Northern blotting
and found, similar to previous reports, that there is a single
major mRNA species of approximately 2.7 kb. By transfecting
cells with a full length cDNA constructs we saw that, like torsin
A, torsin B is subject to N-glycosylation but not O-glycosyla-
tion. Polyclonal antibodies raised against regions of low ho-
mology between torsinA and torsinB were used to confirm that
both proteins are localized to PDI-positive structures in trans-
fected cells, suggesting that both proteins reside in the endo-
plasmic reticulum. When expressed in cell lines, torsinB has
similar electrophoretic mobility to torsinA but is more basic,
consistent with predictions from the cDNA sequence. Using
antibodies designed to a common region of both torsin proteins,
we show that torsinA is much more abundant than torsinB in
human cerebellum brain extracts. These results show that
torsins A and B are similar proteins, although there are sub-
stantial differences in the abundance of the two homologues.
An Epidemiological Survey of Dystonia (ESD) Within the
Entire Population of Northeast England over the Past 9
Years
A.G. Butler,1 P.O.F. Duffey,2 M.R. Hawthorne,3 M.P. Barnes4
1
ADDER, Bath Cottage, Dinsdale Park, Middleton St. George,
Co. Durham; 2York District Hospital, Wigginton Road, York;
3
The North Riding Infirmary, Newport Road, Middlesbrough,
Cleveland; 4University of Newcastle, Hunters Moor Rehabili-
tation, Centre, Hunters Road, Newcastle-upon-Tyne, United
Kingdom
The Epidemiological Survey of Dystonia (ESD) was started
in May 1993 with just 143 people known to have dystonia in
the northeast of England and Cumbria. By the time of the 3rd
International Dystonia Conference (Florida, June 1996), there
were a total of 500+ cases who had been diagnosed, and by
June 2001 the total number of primary and secondary dystonics
was over 1,100 people within the geographical region. The
research has proven that dystonia is the third most prevalent
movement disorder after Parkinsons disease and benign essen-
tial tremor. Each of the cases has been examined by a qualified
neurologist and one of the most rewarding results of the re-
search to date is that there has been a positive identification that
28.7% of all these cases have a proven member of the family
with a form of dystonia, i.e., with a definite and genetic con-
nection within the dystonic family, thus increasing the present
known incidence of familial dystonia. This is the first time that
an epidemiological study has attempted to identify all cases of
dystonia in a well-defined population. All other previous dys-
 4th INTERNATIONAL DYSTONIA SYMPOSIUM
tonia epidemiologies have either taken medical referral centres
as the basis for their statistics or have been flawed in that either
ascertainment of their diagnosis was incomplete or the nature
of their criteria was limited in some way. In this case, a definite
geographical region has been taken and as far as is possible
everyone known to have dystonia who lives or is treated within
that region has been included. Over 12.1% of these people were
not registered at any hospital or medical centre. As previously
reported, Darlington, a small town in the North East of En-
gland, with a known population of 101,766 individuals within
45,383 households was the subject of an intensive epidemio-
logical study undertaken in 1996 (note change in date). This
study has continued to date and currently this town has exactly
53 people within it with a form of dystonia, thus indicating a
prevalence of 1 in 2,000 people (precisely 1 in 1,920). Research
undertaken by Professor E. Altenmuller amongst musicians in
Germany has shown that the prevalence of dystonia could be as
high as 1 in 500. The reason for this may be explained in that
musicians, almost more than any other occupation, make very
fine repetitive movements of the fingers and hands and that
very small dystonic tremors or postures, that are not noticeable,
nor cause a problem in others, can be devastating to them.
Dystonia is not a rare disorder, but it does remain little known
or recognised, even within medical circles. Research, such as
the above, has proven it has a known prevalence of less than 1
in 2,000 people in the general population and even higher in
specialist groups.
Development of a cell-based assay to screen compounds for
resolution of mutant torsinA aggregates
D.C. Bragg, J.D .Wilbur, X.O. Breakefield
Molecular Neurogenetics Unit, Massachusetts General Hospi-
tal, Charlestown, Massachusetts, USA
Most cases of early-onset, generalized torsion dystonia have
been attributed to the deletion of a glutamic acid residue in the
carboxy terminus of torsinA. Previous work in our laboratory
has demonstrated that overexpression of mutant, but not wild-
type torsinA in cultured cells by DNA transfection results in its
accumulation in multilamellar inclusions that appear to derive
from the endoplasmic reticulum. We recently developed an
improved delivery strategy to express either mutant or wild-
type torsinA in cultured cells using herpes simplex virus type 1
(HSV-1) amplicon-based viral vectors. The coding sequence of
either wild-type or mutant torsinA was cloned into an HSV-1
amplicon plasmid and packaged as HSV amplicon vectors us-
ing a helper virus-free system. The resulting vectors contain the
torsinA sequences under the control of the cytomegalovirus
promoter with a separate expression cassette encoding the en-
hanced green fluorescent protein to allow identification of in-
fected cells. These vectors express either wild-type or mutant
torsinA in human glioma cells at extremely high efficiencies
(approximately 80-90% of cells in culture) and at expression
levels which, compared to those achieved by DNA transfection,
more closely resemble those of the endogenous protein. Fol-
lowing infection with these amplicon vectors, cells expressing
mutant, but not wild-type, torsinA also form discrete aggre-
gates that can be visualized via immunofluorescence. Western
blot analysis confirmed that this expression system produces
equivalent levels of either mutant or wild-type protein in in-
1125
fected cells. We have subsequently adapted this approach to a
format compatible with high throughput screening by seeding
infected cells into 384-well microtiter plates, processing for
torsinA immunofluorescence using automated liquid handling
devices, and rapidly capturing digital images of each well with
an automated fluorescent microscope. Digital images are ana-
lyzed using image analysis software (Metamorph; Universal
Imaging, West Chester, PA) to determine both the density and
average size of mutant aggregates per well. This system thus
serves as a sensitive, cell-based assay to evaluate factors that
may resolve the mutant torsinA aggregates, and it is currently
being used to screen a library of FDA-approved compounds
provided by the National Institute of Neurological Disorders
and Stroke (NINDS).
A Drosophila Model of Early-Onset Torsion Dystonia
Y.H. Koh, K. Rehfeld, B. Ganetzky
University of Wisconsin Madison, Madison, Wisconsin, USA
Two mutations in the DYT1 gene, encoding the TorsinA
protein, are linked to early-onset torsion dystonia, the most
common and severe form of this disorder. However, the cellu-
lar and molecular mechanisms of pathogenesis underlying
early-onset torsion dystonia are still not clear and the cellular
functions of TorsinA proteins in the nervous system are still
unknown. We have been utilizing the experimental advantages
of Drosophila (fruit fly) to establish a model for investigating
the cellular and molecular mechanisms of pathogenesis under-
lying early-onset torsion dystonia. To examine Drosophila Tor-
sin (Dtor) functions in vivo, we are using inhibitory RNA
(RNAi) to reduce expression of the Dtor gene by creating trans-
genic lines that express Dtor double-stranded RNA. Immuno-
staining with anti-Dtor antibodies demonstrates that Dtor pro-
tein levels are reduced in neurons and muscles of these flies.
Furthermore, reduction of Dtor expression in these lines is
associated with a signficant alteration in the morphological
appearance of synapses at the larval neuromuscular junction.
Thus, normal levels of Dtor are required either directly or in-
directly for normal synaptic development in Drosophila. In a
complementary approach, we have created transgenic strains of
Drosophila that express either normal human TorsinA (HtorA)
or one of two mutant forms of this protein. Normal and mutant
forms of HTorA were expressed in selected populations of
neurons and muscles to examine the subcellular localization of
HtorA and the effect of expression on synaptic morphology.
Normal HtorA is distributed broadly over neuronal soma or
muscle surfaces. However, mutant Htor containing a single
amino acid deletion exhibits strong clustering of around cellu-
lar membranes in neurons and muscles. Furthermore, expres-
sion of the same mutant protein in motor axons or muscles
induced morphological changes at glutamatergic synapses at
the larval neuromuscular junction. Over-expression of a second
mutant form HtorA, containing a six-aminoacid deletion, in-
duced similar defects in synaptic morphology, even though the
cellular distribution of this mutant protein was more like that of
normal. At present, we are investigating in more detail the
behavioral, morphological and electrophysiological phenotypes
in flies expressing Dtor RNAi and the various forms of Htor.
Movement Disorders, Vol. 17, No. 5, 2002
1126 4th INTERNATIONAL DYSTONIA SYMPOSIUM
III: OTHER GENETIC DYSTONIAS
Classification and Clinical Features
S.B. Bressman
Beth Israel Medical Center, New York, New York, USA
Classification schemes for the many etiologies of dystonia
are under constant revision, reflecting increasing knowledge
about the many genetic causes and widening clinical experi-
ence with specific dystonia genes. Primary (torsion) dystonia
(PTD) has been defined as a group of disorders characterized
clinically by dystonic movements and postures as the only
overt sign except for tremor, and also having no acquired or
exogenous cause or evidence of neural degeneration. The sec-
ondary dystonias are comprised of all other dystonic condi-
tions; these include inherited or complex disorders that may or
may not have neural degeneration and usually manifest other
neurological signs (especially parkinsonism), and exogenous or
environmental etiologies. Primary dystonia consists of at least
5 autosomal dominant disorders, each having reduced pen-
etrance and variable expression. Clinically the primary dysto-
nias can be organized by the predominant family phenotype
into three groups, each having at least one associated genetic
locus: early limb-onset (DYT1), a mixed phenotype with early
and adult onset dystonia usually involving cervical, cranial and
brachial muscles (DYT6 and 13), and adult-onset focal dysto-
nias (DYT7 and at least one other locus). A gene has been
identified for only one of the PTD loci: TOR1A (at locus
DYT1). The clinical spectrum of TOR1A has been amplified in
reports from many ethnically diverse populations and is gen-
erally consistent (with early limb-onset dystonia in most but not
all). The range of dystonia, including the extent of body regions
affected and severity of contractions, is quite variable both
within and among DYT1 families. Further, although dystonia is
expressed in only about 30 to 40% of TOR1A gene carriers,
other features, including abnormal PET resting brain network
patterns and motor sequence learning deficits, may be present
in non-dystonic gene carriers. The reasons for DYT1 variable
expression and reduced penetrance remain unknown.
Genetics of DYT6, DYT7, DYT12, and DYT13
L. Ozelius
Molecular Genetics Department, Albert Einstein College of
Medicine, Bronx, New York, USA
The DYT6 locus was identified by linkage analysis using
Swiss Mennonite families. The clinical picture is broad or
mixed with an early age of onset and progression to involve
multiple body regions. The DYT6 was mapped to a 40cM
region on chromosome 8 with identical haplotypes segregating
in both families, suggesting a common founder. Recent studies
using additional polymorphic markers and a newly ascertained
branch of the family place the gene into a region of about 24.5
cM. Several large families with late-onset PTD have been de-
scribed. One such family, from Northwest Germany, manifests
primarily late-onset focal cervical dystonia (torticollis). This
family was used for linkage studies and a gene, DYT7, local-
ized to a 30 cM region on chromosome 18p. However, linkage
analyses in other clinically similar families have excluded
Movement Disorders, Vol. 17, No. 5, 2002
DYT7, supporting the presence of other as yet unmapped loci.
A genome wide search in a large Italian PTD family with 11
definitely affected members resulted in the identification of a
novel locus, DYT13. The phenotype in this family is charac-
terized by prominent cervical-cranial and upper limb involve-
ment with early onset and mild severity. Linkage and haplotype
analysis placed the locus within a 22 cM interval on the short
arm of chromosome 1. At present, four unrelated families have
been reported with rapid onset dystoniaparkinsonism (RDP,
DYT12). RDP is characterized by abnormal movements typical
of both dystonia and parkinsonism. These symptoms can come
on rapidly (over hours to days) followed by stable symptoms
for years. Using two of the families, a gene for RDP was
mapped to chromosome 19q13 (DYT12) in an 8 cM region
between D19S587 and D19 S900. Both an Irish family with 8
affected individuals and a family from Poland with 4 affected
members have been linkage to the same chromosome 19 locus.
MyoclonusDystonia Syndrome
T. Gasser
Department of Neurology, Klinikum Grosshadern, Ludwig-
Maximilians-University Munich, Munich, Germany
Myoclonusdystonia syndrome (MD) is an autosomal dom-
inant disorder characterized by bilateral, alcohol-sensitive myo-
clonic jerks involving predominantly the arms, neck, and axial
muscles and relatively mild dystonia (usually torticollis and/or
writers cramp) in some affected individuals. Onset of abnor-
mal movements is usually in the first or second decade of life.
In addition to motor symptoms, patients often show psychiatric
abnormalities, including panic attacks and obsessive
compulsive behavior and alcohol abuse. The disease has been
mapped to a locus on chromosome 7q21 by Nygaard and co-
workers and this finding has been confirmed by several groups
in at least 8 families, indicating that this appears to be the major
locus responsible for this phenotype. Recently, we have iden-
tified five different heterozygous loss-of-function mutations in
the gene for epsilon-sarcoglycan (SGCE) in six German fami-
lies with MDS. This finding was surprising, as the four other
members of the sarcoglycan family of genes (, , , and
sarcoglycan) so far had been implicated only in autosomal-
recessive limb girdle muscular dystrophies. The mechanism, by
which mutations in the SGCE-gene cause MDS is unknown.
All mutations published so far are likely to lead to a loss of
protein function. In addition, the inheritance pattern of MDS
indicates that inactivation of one parental allele may contribute
to -sarcoglycan deficiency. Pedigree analysis in MDS-families
showed a marked difference in penetrance depending on the
parental origin of the disease allele, with reduced penetrance
occurring predominantly if the disease allele is passed on by the
mother. This pattern is suggestive of a maternal imprinting
mechanism (i.e., inactivation of the maternally inherited allele,
presumably by methylation) which has already been demon-
strated in the mouse -sarcoglycan gene. This hypothesis is
supported by the observation, that the SGCE-gene is in fact
differentially methylated in humans (M. Grabowski, unpub-
lished results). Furthermore, preliminary rtPCR-experiments
indicate that only one parental allele appears to be preferen-
tially expressed (A. Zimprich, unpublished observations).
 4th INTERNATIONAL DYSTONIA SYMPOSIUM
Nondystonic Features of Hereditary Dystonia
R. Saunders-Pullman
Beth Israel Medical Center, New York, New York, USA
The penetrance of dystonia genes is incomplete: DYT1 is
autosomal dominant with 30 to 40% penetrance. DYT5 is au-
tosomal dominant with 30% penetrance and female-to-male
ratio of 23:1 and DYT11 is autosomal dominant with un-
known reduced penetrance, and penetrance is increased with
paternal transmission. Penetrance is dependent on phenotype,
however, and if our understanding of phenotype changes, in
particular if non-dystonic features are also an expression of
dystonia genes, then penetrance estimates also change. There
are many possible modifiers of dystonia genes, including en-
vironmental, other epigenetic factors, gender and genetic modi-
fiers. In evaluating secondary dystonia and DYT1, Bressman
demonstrated that perinatal asphixia and neuroleptic use appear
not to be triggers for expression of DYT1, measles may be a
modifier, and the role of peripheral trauma is unclear. If early
environmental modifiers play a role in expression of DYT1
they may alter neuronal plasticity in early childhood leading to
decrease in torsin A to subthreshold levels during a vulnerable
window. To test whether early childhood illness was associated
with manifesting DYT1, a self-administered standardized ques-
tionnaire was given to DYT1 family members studied, in whom
gene status and neurological exam status was known. We found
that earlier age of varicella, measles and fever greater than 1
week were associated with manifesting dystonia (P < 0.029,
0.06, and 0.023, respectively) but not mumps (P < 0.078).
Therefore infection may influence penetrance and expression
of dystonia. DYT11 also has reduced penetrance, presumed
secondary to a mechanism of maternal imprinting, such that
transmission through the mother leads to inactivation of the
allele and non-expression. However, this penetrance pattern is
incomplete with some individuals inheriting the maternal allele
expressing symptoms, and others with the paternal allele not
expressing. We previously demonstrated that obsessive
compulsive disorder and alcohol abuse may be associated with
carrying the DYT11 gene, and therefore may be part of the
phenotypic spectrum of DYT11. In three families studied, we
found that broadening the phenotype to include any psychiatric
features did not improve sensitivity and specificity of the im-
printing model, however limiting to obsessivecompulsive dis-
order and alcohol dependence did. Therefore, better under-
standing the phenotypic spectrum may improve our under-
standing of penetrance.
Dopa-Responsive Dystonia
Y. Furukawa
Movement Disorders Research Laboratory, Centre for Addic-
tion and Mental Health-Clarke Division, Toronto, Ontario,
Canada
Dopa-responsive dystonia (DRD) is a syndrome character-
ized by childhood-onset dystonia and a dramatic and sustained
response to low doses of levodopa. There are two known types
of DRD: autosomal dominant GTP cyclohydrolase I (GTPCH)-
deficient DRD caused by GCH1 mutations and autosomal re-
cessive tyrosine hydroxylase (TH)-deficient DRD due to TH
mutations (the mild form of TH deficiency). GTPCH catalyzes
the first step in the biosynthesis of tetrahydrobiopterin (BH4;
the essential cofactor for TH). Many DRD patients, including
1127
apparently sporadic cases, have shown GCH1 mutations. How-
ever, no mutations in the coding region (including the splice
sites) of GCH1 were found in approximately 40% of DRD
families, using conventional genomic DNA sequencing of this
gene. Only several patients with DRD have been reported to
have TH mutations. Thus, because not all DRD patients have
demonstrated mutations in the coding region of GCH1 or TH,
the present DNA testing for DRD is not suitable for routine
clinical practice. A therapeutic trial with levodopa is still the
most practical approach to the diagnosis of DRD. Neuropath-
ological studies showed no Lewy bodies and a normal popu-
lation of cells with reduced melanin in the substantia nigra of 2
patients with GTPCH-deficient DRD. There have been no re-
ports of autopsied patients with TH-deficient DRD. Neuro-
chemical data suggest that striatal dopamine reduction in
GTPCH-deficient DRD is caused not only by decreased TH
activity resulting from a low cofactor level but also by actual
loss of TH protein without nerve terminal loss. In GTPCH-
deficient DRD, striatal TH protein loss may be due to a dimin-
ished regulatory effect of BH4 on the steady-state level of TH
molecules. Recent findings of only modest reduction of TH
protein and dopamine despite marked reduction of total biop-
terin (most exists as BH4) in the putamen of an asymptomatic
GCH1 mutation carrier suggest that the extent of striatal TH
protein loss may play a critical role in determining the symp-
tomatic state of GTPCH-deficient DRD. Notwithstanding the
discovery of GCH1 and TH mutations responsible for DRD,
there remain many important unresolved issues regarding this
treatable disorder, including questions of gender-related incom-
plete penetrance and intrafamilial phenotypic variation (e.g.,
adult-onset benign parkinsonism). A clarification of the
mechanism of striatal TH protein loss in GTPCH-deficient
DRD may provide a new clue to the pathogenesis of this major
form of DRD.
Cloning of the Gene Defect Responsible for X-linked
DystoniaParkinsonism (XDP; lubag): Clinical and Patho-
logical Aspects of X-linked DystoniaParkinsonism
A. Singleton
National Institutes of Health, Bethesda, Maryland, USA
XDP is believed to originate ancestrally from the Filipino
island of Panay, the mean age of onset of symptoms in Lubag
is 35 years, with cases reported from the age of 12 to 48 years
of age. Presenting features often include blepharospasm, torti-
collis, other focal dystonias, and dystonic tremor. When it oc-
curs, focal dystonia invariably progresses to either multi-focal
or generalized dystonia. In addition a common characteristic of
the disease is the presence of Parkinsonian features (40% of
cases examined). We have performed haplotype analysis on 50
affected individuals, their nuclear families and controls. A co-
segregating haplotype has been found in all cases to date. We
have failed to demonstrate the flanking recombinant events at
DXS559 and DXS6673E 3shown previously and thus our seg-
regating region is approximately 200-kb larger. We have se-
quenced the coding region of all of the known genes within the
critical region including ZNF261, p54nrb, OGT, CCG1, CKR-
L2, melusin, NAAR1, and GJP-1B. We amplified the full-
length cDNAs from ZNF261, CCG1, OGT, melusin, p54nrb
and CKR-L2 in an adult and fetal cDNA library and in lym-
phocyte DNA from an XDP case, his mother and an unrelated
control. We have performed northern blot analysis of these
Movement Disorders, Vol. 17, No. 5, 2002
1128 4th INTERNATIONAL DYSTONIA SYMPOSIUM
genes on RNA from a case and a control. No alterations in
coding sequence, splicing or expression have been found to
date.
A Novel DDP Gene Mutation that Causes Dystonia in Fe-
male Carriers of the Mohr-Tranebjaerg Syndrome.
R.H. Swerdlow, V.C. Juel, and G.F. Wooten
Department of Neurology, University of Virginia Health Sys-
tem, Charlottesville, Virginia, USA
Sex-linked male deafness and dystonia (the Mohr-
Tranebjaerg syndrome) arises from aberrant expression of the
DFN-1 gene product, deafness/dystonia peptide (DDP). We
now describe a novel guanine deletion at nucleotide 108 of the
DDP gene in a family with X-linked male deafness and dysto-
nia, which terminates this 97 amino acid protein at codon 25.
Unlike previously reported kindreds, carrier females in this
family also manifest dystonias, including torticollis and writ-
ers cramp. Female carriers do not, however, manifest hearing
loss. A family history of male deafness should alert clinicians
to the possibility of DDP mutation in women with focal dys-
tonias. As DDP is a translocator of the inner mitochondrial
membrane and plays a role in mitochondrial protein import,
genetic studies of sporadic dystonia should consider the
broader family of mitochondrial translocase peptides.
Two Forms of Focal Dystonia are Associated with Polymor-
phisms in the Dopamine-5 Receptor Gene
A. Misbahuddin,1 M. Placzek,1 K. Bhatia,2 K. Ray Chaudhuri,3
N. Wood,2 T.T. Warner1,2
1
Department of Clinical Neuroscience, Royal Free and Uni-
versity College Medical School, London; 2Institute of Neurol-
ogy, London; 3Kings College Hospital, London, United King-
dom
Background: There is increasing evidence that dystonic
movements may be the result of abnormal dopamine neuro-
transmission in the cortico-motor basal ganglia circuits. Genes
causing generalized primary torsion dystonia (DYT1) and
dopa-responsive dystonia (GTP-cyclohydrolase 1) appear to ef-
fect nigral dopaminergic function. Dopamine receptor blocking
drugs are well known to cause tardive dystonia, and dystonic
movements can be produced in primates treated with the nigral
toxin MPTP. In addition a SPECT study showed evidence of
decreased striatal D2 receptor binding in cases of cervical dys-
tonia (CD). Focal dystonia is the commonest form, and most
cases appear to be sporadic although there are some families
with clear autosomal dominant inheritance pattern. The precise
cause of focal dystonia is unknown. Objectives: To assess
whether polymorphisms in the dopamine receptor and trans-
porter genes are associated with development of sporadic CD
or blepharospasm. Methods: A case control allelic association
study of 100 patients with CD and 90 patients with blepharo-
spasm and control groups of 100 individuals using polymor-
phisms within the D1-5 receptor and dopamine transporter
gene. Results: No association was found between patient and
control polymorphism allele frequency for D1-4 receptors and
dopamine transporter. However significant results were ob-
tained with the D5 receptor microsatellite for both CD and
Movement Disorders, Vol. 17, No. 5, 2002
blepharospasm. Allele 2 was found to be positively associated
with both conditions and allele 6 was significantly more fre-
quent in the control group as compared to CD patients. This
latter association remained significant after Bonferroni correc-
tion. Conclusion: The significant association of focal dystonia
with an allele in the D5 receptor gene may indicate a patho-
genic or susceptibilty role of this gene. It is known that D5
receptor gene mRNA is expressed in the substantia nigra pars
compacta supporting the hypothesis that a functional varient of
the D5 receptor could influence basal ganglia dopaminergic
neurotransmission.
Mutation Analysis of the Epsilon-Sarcoglycan Gene in 15
Families with MyoclonusDystonia
P. de Carvalho Aguiar,1,2 L. Liu,1 N. Kock,3,4 B. Mueller,3,4 D.
Raymond,5 J. Harris,6 D. Doheny,7 S. Frucht,6 B. Ford,6 T.
Lynch,6 D. deLeon,5 J. Garrels,3,4 E. Schwinger,4 M. Brin,7 R.
Kurlan,8 A. Lang,9 S. Fahn,6 R. Saunders-Pullman,5 V.
Borges,2 H.B. Ferraz,2 J. Friedman,10 S. Fahn,6 C. Klein,3,4 S.
Bressman,5 L. Ozelius1
1
Molecular Genetics Department, Albert Einstein College of
Medicine, New York, New York, USA; 2Department of Neurol-
ogy and Neurosurgery, Federal University of So Paulo, So
Paulo, Brazil; Departments of 3Neurology and 4Human Genet-
ics, Medical University of Lbeck, Lbeck, Germany; 5Depart-
ment of Neurology, Beth Israel Medical Center, New York, New
York, USA; 6Department of Neurology, Columbia University,
New York, New York, USA; 7Department of Neurology, Mount
Sinai School of Medicine, New York, New York, USA; 8Depart-
ment of Neurology, University of Rochester School of Medi-
cine, Rochester, New York, USA; 9Division of Neurology, De-
partment of Medicine, University of Toronto and the Toronto
Western Hospital, Toronto, Ontario, Canada; 10Department of
Neurology, Massachusetts General Hospital, Boston, Massa-
chusetts, USA
Discovery of the causative gene revealed broadness of phe-
notypical variation of HPD/DRD. It had been shown that the
rates of mutant /wild type GCH-1 in RNA in lymphocytes vary
in one mutation and differ depending on the locus of mutation
[Hirano et al., Ann Neurol 1998;44:365371]. Thus, we as-
sessed the incidence of familial occurrence, interfamilial varia-
tion of symptoms and presence of atypical phenotypes in fami-
lies of gene-proved HPD/DRD and evaluated their correlation
to the loci of mutations. In atypical phenotypes we included
dystonic cramp, axial torsion, spontaneous remission, occulo-
gyric crisis, action dystonia, focal dystonia and early onset in
infancy with delay in motor milestones. Fifty-one families, in-
cluding 13 personal ones with precise description of clinical
symptoms and the pedigree were subjected to this study. Pa-
tients with compound heterozygotes were excluded from this
study. Of them 46 had mutations in coding regions, 20 in exon
1, 7 in exon 2, 1 in exon 3, 4 in exon 4, 7 in exon 5 and 7 in
exon 6 and 5 in introns, one in intron 1, 2 each in intron 2 and
3. Seventeen of 51 families had familial occurrence. In personal
families, it was 5 out of 13; 2/4 in exon 1, 1/2 in exon 2, 0/2 in
exon 4, 1/2 in exon 5, 1/1 in exon 6 and none of 3 families with
mutation in intron. They were 10/20 in exon 1, 5/7 in exon 2,
1/1 in exon 3, 1/4 in exon 4, 3/7 in exon 5 and 6/7 in exon 6.
Among families with mutation in intron one in intron 3 had
 4th INTERNATIONAL DYSTONIA SYMPOSIUM
familial occurrence. As for intrafamilial variation, mild antici-
pation was observed in families with mutation in the exon 1 and
marked variation without any relation to the generation in fami-
lies with abnormalities in exon 5 and 6. As for the phenotypes
shown after the discovery of the gene dystonic cramp and toti-
collis had no preference to particular loci of the mutation. How-
ever, except for patients with a mutation in intron 3, patients
with occulogyric crisis, action dystonia and focal dystonia were
observed in those with mutation in the exon 6. Delay in devel-
opmental motor milestones with hypotonia and abnormalities
in locomotion, as well as occulogyric crisis observed in patients
with compound heterozygote may be due to hypofunction of
the serotonergic neurons caused by marked reduction of the
tetrahydrobiopterin (BH4). DYT-1 has two phenotypes depend-
ing on families, one is postural dystonia and the other is action
dystonia and the upper generation of the latter has patients with
focal dystonia. These suggest phenotypical variation depend on
the grade of reaction of BH4 and/or difference of the involved
neuronal pathways, both of which might depend on the varia-
tion of gene abnormalities. Thus, these results imply that the
each loci of GCH-1 gene has particular modulation in the pteri-
din metabolism and affect particular NS-DA neurons and path-
ways of the basal ganglia which is involved in pathophysiolo-
gies for various types of dystonia.
Evaluation of GRIK5 (KA2) as a Candidate Gene for
Rapid-Onset DystoniaParkinsonism (RDP, DYT12)
C. Kamm,1 J. Leung,1 A. Brashear,2 W. Dobyns,3 X. Break-
efield,1 L. Ozelius4
1
Molecular Neurogenetics Unit, Massachusetts General Hos-
pital, and Department of Neurology and Genetics and Neuro-
science Program, Harvard Medical School, Boston, Massachu-
setts; 2Department of Neurology, Indiana University School of
Medicine, Indianapolis, Indiana; 3Department of Human Ge-
netics, Neurology and Pediatrics, University of Chicago, Illi-
nois; 4Department of Molecular Genetics, Albert Einstein Col-
lege of Medicine, Bronx, New York, USA
Rapid-onset dystoniaparkinsonism (RDP) is a rare autoso-
mal dominant movement disorder characterized by abrupt onset
of persistent dystonia and parkinsonism, generally during late
childhood or early adulthood, with little or no progression
thereafter. Recently, linkage of this disease to an 8cM region on
chromosome 19q13 (DYT12) has been reported. One of the
candidate genes in this region, GRIK5, encodes a kainate-type
glutamate receptor subunit, KA2. In rat brain, KA2 mRNA is
expressed at high levels in the basal ganglia, especially in the
striatum, substantia nigra pars compacta and subthalamic
nucleus, regions that are critically involved in movement con-
trol. Given that corticostriatal glutamatergic neurons form the
major afferent projection to the striatum, the KA2 subunit could
act by modulating dopaminergic input into the striatum. There-
fore, in order to evaluate the role of this gene in rapid-onset
dystoniaparkinsonism, we performed mutational analysis in
two previously described RDP families with linkage to 19q13.
Screening of GRIK5 exons 219 and a 300-bp region within
intron 1, which has previously been shown to downregulate
expression of the rat GRIK5 gene, in 2 patients from each
1129
family did not identify any changes in nucleotide sequence
compared to healthy controls. This indicates that RDP in these
families is not caused by mutations in either exons 219 or in
a putative negative regulatory region within intron 1 of the
GRIK5 gene.
Sporadic and Familial Primary Torsion Dystonia Cases in
Italy
A. Elia,1 E. Lo Schiavo,1 E. Cassetta,1,2 T. Ialongo,1 E.M.
Valente,1,3 A.R. Bentivoglio,1 A. Albanese1,4
1
Istituto di Neurologia, Universit Cattolica, Rome; 2Ospedale
Fatebenefratelli, Rome; 3Istituto Mendel, Rome; 4Istituto Na-
zionale Neurologico, Milan, Italy
The Gemelli dystonia registry encompasses 593 cases of
dystonia out of a series of 4581 patients with movement dis-
orders. They originate from all Italian regions, but the majority
is from Central and Southern Italy. Familial and sporadic pri-
mary torsion dystonia (PTD) cases were grouped based on
phenotype. Genetic analysis was performed using currently
available techniques. 460 PTD patients (296 women, 164 men)
were followed up for an average of 2.4 3.2 years. Their mean
age at onset was 48.3 17.7; disease duration was 13.7 9.0
years. Cranial, cervical or lower limb onset were more frequent
in women (male-to-female ratios 1:2.7, 1:1.9, 1:3, respec-
tively); the same prevalence occurred for cases who remained
focal at follow-up (male-to-female ratios 1:2.3 for cranial, 1:1.9
for cervical, 1:2 for lower-limb PTD). In addition, the mean age
at disease onset was higher in women in the focal forms listed.
By contrast, upper limb PTD had a higher incidence in men
(male-to-female ratio 2.2:1) and also a higher age at onset in
men. At last visit, 269 PTD patients were still affected by focal
dystonia, 159 by segmental dystonia, 7 by multifocal dystonia
and 25 by generalized dystonia. In all, 41.5% had clinical pro-
gression. When comparing patients grouped by body district
affected at onset. A clinical progression was found in PTD
cases with cranial onset (41.1%), cervical (45.3%), upper limb
(29.6%), or lower limb onset (75%). Familial aggregation was
found in 80 (17.4%) of 460 PTD cases (mean age at onset, 44.6
19.3 years). 39 PTD families were studied: 15 presented a
prevalently focal phenotype, 16 a prevalently segmental, and 8
a generalized phenotype. Age of onset was juvenile in all fami-
lies with generalized PTD and adult in the other ones. Twenty-
two family probands were tested for DYT1 mutation and 3 of
these resulted carriers of GAG deletion of DYT1 gene: all
presented generalized dystonia with early limb-onset and rapid
generalization. No DYT1 patient carried the novel 18-bp dele-
tion. The prevalent (20.1% of families) phenotype of non-
DYT1 familial cases was cranial-cervical dystonia with occa-
sional limb dystonia (cranial-cervicalplus dystonia). Isolated
cranial-cervical dystonia was found in 16.5% of familial cases,
focal cervical dystonia in 5.5%, cervical dystonia with limb
involvement (cervical-plus dystonia) in 17.4%, Meiges syn-
drome in 4.6%, blepharospasm in 7.3%, laryngeal dystonia in
8.2% and writers cramp in 3.6%. Generalized dystonia oc-
curred in 16.5% of familial cases and mioclonic dystonia in
5.5%. Focal oromandibular or lower limb dystonia did not rep-
resent a phenotype observed in familial aggregation. The
cervical-plus group included a large family with 11 affected
members linked to a novel PTD locus (DYT13) located on
chromosome 1p36.13-36.32.
Movement Disorders, Vol. 17, No. 5, 2002
1130 4th INTERNATIONAL DYSTONIA SYMPOSIUM
A Screen of GTP Cyclohydrolase I in Parkinsons Disease
Patients
C. Evey,1 M. Hanson,1 A. Singleton,2 K. Gwinn-Hardy,2 M.
Farrer,3 A. Singleton4
1
Laboratory of Neurogenetics, National Institute on Aging,
NIH, Bethesda, Maryland; 2Neurogenetics Branch, National
Institute of Neurological Disorders and Stroke, NIH, Bethesda,
Maryland; 3Mayo Clinic Jacksonville, Jacksonville, FL;
4
Laboratory of Neurogenetics, National Institute on Aging,
NIH, Bethesda, Maryland, USA
Dopa-responsive dystonia (DRD), mapped to chromosome
14q22.1-q22.2, is associated with mutations of the GTP cyclo-
hydrolase I (GCH-I) gene. GCH-I is the rate-limiting enzyme in
the synthesis of tetrahydrobiopterin (BH4), which is required
for the synthesis of L-dopa by tyrosine hydroxylase (TH). DRD,
both an autosomal dominant and recessive disorder, is charac-
terized by childhood or adolescent onset of dystonia sometimes
associated with parkinsonism, and response dramatically to low
doses of L-dopa. Presently, up to 60 mutations in GCH-I have
been reported in DRD patients. It has been demonstrated that a
single heterozygotic mutation in GCH-I may result in less than
50% of normal activity via a postulated dominant-negative
mechanism. This decrease of GCH-I activity may lead to di-
minished dopamine production, which could then result in
clinical manifestations of DRD. Furthering this concept, abnor-
malities in GCH-I may also help to explain the cause of other
neurodegenerative disorders that result from dopamine defi-
ciency, such as Parkinsons disease. Thus, we have undertaken
a screen of the GCH-I gene in 330 cases of Parkinsons disease
patients with a family history. Genetic identification of muta-
tions may provide insight into the varying expressivities of
GCH-I mutations.
Spinal Cerebellar Ataxia 8 Presenting with Dystonia
S. Gauthier and M. Saint-Hilaire
Boston University Medical Center, Boston, Massachusetts,
USA
The spinal cerebellar ataxias are a heterogeneous group of
disorders that are distinct syndromes classified by their genetic
locus. The original description of the spinal cerebellar ataxia 8
phenotype included spastic and ataxic dysarthria, nystagmus,
limb and gait ataxia, limb spasticity, and diminished vibration
perception. Case reports following the original description, re-
mained with a predominant syndrome of pyramidal tract in-
volvement, ataxia, and a mild axonal neuropathy. Extrapyra-
midal involvement has not been described to be a main feature
of spinal cerebellar ataxia 8 in any families studied. The only
previously reported extrapyramidal symptoms were mild ath-
etotic movements of the fingers in 4 patients of a seven-
generation family. We report on a patient with a neck dystonia
as a novel presentation for spinal cerebellar ataxia 8. His symp-
toms began at the age of 28 with episodic head twitching and
dysarthria. These symptoms progressed over an 8-year period,
at which time, he was found to have limb ataxia. On examina-
tion, the patient had intermittent turning of his head to the right,
dysarthria, and limb ataxia. After an extensive workup, he was
found to have 135 CTA/CTG repeats for the SCA8 mutation.
Movement Disorders, Vol. 17, No. 5, 2002
Sequencing Strategies to Identify Segregating Alterations in
X-Linked DystoniaParkinsonism
S. Hague, D. Hernandez, J. Hardy, A. Singleton
Laboratory of Neurogenetics, National Institute on Aging, NIH,
Bethesda, Maryland, USA
The X-linked recessive dystoniaparkinsonism syndrome
(XDP) is a severe progressive disease presenting with focal
dystonia, progressing to a generalized form with concomitant
parkinsonism in 50% of cases. XDP originated from a common
ancestor in the Filipino population and is particularly prevalent
on the Philippine island of Panay. XDP is inherited in an
X-linked recessive manner, consequently the vast majority of
cases are male. Linkage and allelic association studies have
assigned the gene to a 350kb interval on the X chromosome
residing to the Xq13.1 region between the markers DXS6673E
and DXS559, a region of approximately 350 kb. Intense efforts
to clone the defective gene have proved difficult. The exons
and introns of a number of genes residing in this critical region
have been sequenced and as yet no causative mutation has been
detected. Additionally, the upstream regulatory regions of these
genes have been sequenced and no mutations detected. In an
attempt to identify the mutation responsible for XDP we have
produced a Cosmid library from an XDP affected male. The
library contains the 350 kb critical region and additional up-
stream and downstream sequence. The cosmid library has been
shotgun cloned into a plasmid vector and is presently being
sequenced and a contig of the entire region constructed. Elu-
cidation of the causative genetic defect in XDP will not only
provide a therapeutic target for the treatment of this disease but
will provide an insight into the mechanisms involved in other
dystonias.
Identification and Screening of Candidate Genes Within
the X-linked Recessive DystoniaParkinsonism Critical
Region
D.G. Hernandez,1 V. Evidente,2 A. Jhoe-Anthony,3 F. Nativi-
dad,3 J. Hardy,1 A. Singleton1
1
Laboratory of Neurogenetics, National Institute on Aging,
NIH, Bethesda, Maryland, USA; 2Mayo Clinic, Scottsdale, Ari-
zona, USA; 3St Lukes Hospital, Quezon City, The Philippines
Background: X-linked dystoniaparkinsonism (XDP) is a re-
cessively inherited, severe, adult-onset movement disorder. It is
characterized by dystonia, predominantly focal at presentation,
progressing to a generalized form with co-incidental parkin-
sonism in about 50% of the cases. XDP is believed to originate
from a common ancestor in the Philippine island of Panay.
Linkage and allelic association studies have mapped the gene
defect causing this disorder to a small interval in Xq13.1. This
interval of approximately 300kb is flanked by the markers
DXS6673E and DXS559. Objective: To identify the disease
causing mutation within the XDP critical region, and to pro-
duce a comprehensive physical map of the candidate region
associated with XDP to facilitate identification and analysis of
all candidate genes. Methods: We have performed haplotype
analysis on affected individuals, their nuclear families and con-
trols. We have used an electronic database mining and posi-
tional cloning strategy to identify genes within the critical re-
gion and have constructed a physical map of the candidate
region using a series of BACs, PACs and cosmids. We have
sequenced all eight genes in XDP cases and their mothers.
 4th INTERNATIONAL DYSTONIA SYMPOSIUM
Additionally, we have sequenced the coding exons of one gene
centromeric to the candidate region, gap junction protein 1b
(GJP 1b). We have examined full-length gene transcripts from
all eight genes amplified in adult and fetal cDNA libraries,
lymphocyte DNA from both an XDP case and his mother and
an unrelated control. Results: Although a co-segregating hap-
lotype has been found in all cases to date, we have yet to
demonstrate the flanking recombinants at DXS559 and
DXS6673E3 previously reported by Nemeth et al. In addition
to identifying previously mapped genes, we have examined
four more full-length genes within the critical region, melusin,
FLJ23071, CKR-L2 and Neuroligin 3 (NLGN3.) We have yet
to find any coding changes within these genes that segregate
with disease; however, we have identified a polymorphism in
the Neuroligin 3 gene that segregates with diesease in all XDP
cases. We have examined a large number of XDP patients in
order to define the minimal segregating haplotype. We have
sequenced known and novel genes within the candidate region
but have not found a segregating mutation. In addition to iden-
tifying and sequencing the promoter regions of each gene, we
are currently utilizing a number of strategies aimed at identi-
fying new genes in and around the candidate region.
Novel Animal Models for Paroxysmal Dystonia
H.A. Jinnah, Z. Khan, L. Rao, M.Y. Shin, B.E. Fureman, E.J.
Hess
Johns Hopkins Hospital, Baltimore, Maryland, USA
The paroxysmal dyskinesias include a rare group of disor-
ders characterized by intermittent attacks of involuntary abnor-
mal movements unassociated with any epileptiform activity in
EEG recordings. The movements are often dystonic or chorei-
form, but may include a variety of other abnormalities. The
paroxysmal dyskinesias are currently divided into three groups,
based on triggers of attacks, attacks duration, predominant mor-
phology, and other features. The pathophysiology of this un-
usual group of disorders is currently not well understood. Ani-
mal models can provide valuable tools to investigate the patho-
physiology of human disease. The only well-described animal
model for paroxysmal dyskinesia is an inbred line of golden
Syrian hamsters, which display predominantly dystonic dyski-
nesias in response to stress and other influences. The cause of
paroxysmal dyskinesias in these hamsters remains unknown. In
recent studies, we identified the existence of paroxysmal dys-
kinesias in two strains of mice, each carrying a defined muta-
tion affecting voltage-regulated calcium channels. As the first
step in characterizing the paroxysmal dyskinesias in these mice,
we developed quantitative methods for measuring the fre-
quency, morphology, and severity of the attacks. We also per-
formed digital videotaping and telemetry to quantify cortical
EEG changes associated with attacks in freely moving animals.
The tottering mouse carries a point mutation in the CACNA1A
gene, which encodes the pore-forming subunit of brain P/Q-
type calcium channels. These mice display absence epilepsy,
mild ataxia, and intermittent attacks of severely disabling motor
dysfunction. The motor attacks can be reliably triggered by
stress or caffeine, occur several times per day, last 40 to 60
minutes, and have a predominantly dystonic morphology. The
lethargic mouse carries an insertion mutation in the CACNB4
gene, which encodes the -4 subunit of brain P/Q-type calcium
channels. These mice display absence epilepsy, mild ataxia,
hypokinetic motor behavior, and intermittent motor attacks.
1131
Like tottering mice, the motor attacks in lethargic mice have a
predominantly dystonic morphology. However, other features
of the attacks in lethargic mice are quite distinct from those of
tottering mice. Attacks in lethargic mice are triggered by ex-
ercise or caffeine, occur hundreds of times per day, and last
only between 4 and 8 minutes. Even when performed by a
blinded observer, the quantitative methods were readily capable
of discriminating between the two genotypes. Quantitative
EEG revealed frequent 6 Hz polyspike discharges in both of the
mutants. However, their motor attacks were not associated with
any change in the frequency of these polyspike discharges or
the power spectrum. The phenomenology and lack of EEG
correlates confirm that the motor attacks in tottering and le-
thargic mice reflect paroxysmal dyskinesia rather than motor
epilepsy. These studies demonstrate paroxysmal dyskinesias in
mice to result from a channelopathy affecting P/Q-type calcium
channels. These mice provide valuable new tools to investigate
the pathophysiology of the paroxysmal dyskinesias and raise
the possibility that paroxysmal dyskinesias in humans may re-
flect also dysfunction of ion channels. [Note: This work was
supported by the National Institutes of Health (NS40470 and
NS33592).]
Is Phenotypic Variation of Hereditary Progressive Dystonia
with Marked Diurnal Fluctuation/Dopa-Responsive Dysto-
nia Caused by Difference of the Locus of Mutation on the
GTP Cyclohydorolase 1 Gene?
M. Segawa,1 S. Yukishita,1 K. Hoshino,1 K. Hachimori,1 Y.
Nomura,1 N. Nishiyama,2 H. Ichinose,3 M. Yokochi4
1
Segawa Neurological Clinic for Children, Tokyo; 2Gradu-
ate School of Pharmaceutical Sciences, University of Tokyo, Tokyo;
3
Institute for Comprehensive Medical Science, Fujita Health Univer-
sity, Toyoake, Aichi; 4Department of Neurology, Tokyo Metropolitan
Ebara Hospital, Tokyo, Japan
There are broad phenotypic variations in HPD/DRD. The
ratio of mutant to wild-type mRNA of GCH-1 varies in one
mutation and differ depending on the locus of mutation. Thus,
we assessed the incidence of familial occurrence, inter-and
intra-familial variation of symptoms and atypical phenotypes in
families of gene-proved HPD/DRD and correlated them to the
mutation loci. Evaluated atypical phenotypes were dystonic
cramp, oculogyric crisis, action dystonia, focal dystonia, delay
in motor milestones and spontaneous remission. Sixteen fami-
lies with 32 patients (27 women, 5 men) personally examined
were subjected to this study. Six families had mutations in exon
1, 2 in exon 2, 2 in intron 3, 2 in exon 4, 1 in intron 4, 2 in exon
5 and 1 in exon 6. Onset years slightly differed among muta-
tions; 6.1 2.4 in exon 1, 6.4 3.1 in exon 2 and 7.7 2.1 in
exon5. One patient with mutation in intron 3 had onset at 58
years, the other 4 had onset at 6.6 2.6. One each in intron 4
and exon 6 developed the symptoms at 13 and 7 years, respec-
tively. Eleven families had familial cases. Anticipation was
observed in symptomatic cases in 5 families; 2 in exon 1 and
one each in exon 2, intron 3 and intron 4. Marked intra-familial
variation in the grade of symptoms was observed in a family of
exon 5. There were 5 sporadic cases: two in exon 1 (including
one de novo case), 2 in exon 4 and one in exon 6. Dystonic
cramp was observed in 5 (3 in exon 1, one each in exon 2 and
5), action dystonia in 4; one with oculogyric crisis in intron 3,
2 in exon 2 and one in exon 6. Torticollis was observed in 4
(one each in exon 1, 2, 6 and intron 4). One in exon 5 had
Movement Disorders, Vol. 17, No. 5, 2002
1132 4th INTERNATIONAL DYSTONIA SYMPOSIUM
spontaneous alleviation in the puberty. Levodopa induced dys-
kinesia in a female (T.O.), an elder sister of a patient with
mutation in exon 1. No patient showed delay in development of
motor milestones. All examined patients had characteristics of
HPD/DRD basically. Minor variations, started with arm dys-
tonia or hand tremor were observed in patients with ages at
onset over 8 years. No patients showed tremor in their clinical
course if levodopa was administered before this age. Thus there
are age-related variations. Dystonic cramp as well as torticollis
was observed together with action dystonia. Two patients, 1
with oculogyric crisis with mutation in intron 3 and the other in
exon 6 were shown to have a different pathophysiology than
classical HPD/DRD by the polysomnographyies. Thus, action
dystonia as well as dystonic cramp and torticollis may be phe-
notypic variation related to the loci of mutation. The case T.O.
reported by Narabayashi and Yokochi had similar neurohisto-
chemical findings as HPD/DRD, but with some neruopatho-
logical findings suggesting pathology of Parkinsons disease.
She as well as her brother had clinical characteristics similar to
HPD/DRD. The particular neuropathological changes might be
caused by huge dosis of levodopa.
IV. POSITRON EMISSION TOMOGRAPHY AND BIO-
CHEMISTRY OF DYSTONIA
Abnormal Brain Function in Nonmanifesting DYT1
Carriers
D. Eidelberg and M. Carbon
Center for Neurosciences, North Shore-LIJ Research Institute,
New York University School of Medicine, Manhasset, New
York, USA
Background: In an earlier metabolic PET study we identified
an abnormal resting metabolic brain network in neurologically
normal NM-DYT1. We have previously reported abnormalities
in sequence learning in NM-DYT1. In normals performing se-
quence learning tasks, target acquisition is associated with ac-
tivation of the striatum, DLPFC, preSMA, and anterior cingu-
late; target retrieval is associated with activation of the premo-
tor cortex, the precuneus, and the right posterior parietal cortex.
In this study, we scanned NM-DYT1 subjects with H215O/PET
to determine whether abnormal activation of these regions is
the basis for the sequence learning abnormality. Objective: To
use PET to determine the basis for abnormal motor sequence
learning in non-manifesting carriers of the DYT1 mutation
(NM-DYT1). Methods: 7 right-handed NM-DYT1 (age 50.8
13.2 years) and 7 age-matched normal controls were scanned
while moving their dominant hand on a digitizing tablet at 1
Hz. All subjects performed two kinematically controlled motor
tasks:1.Motor execution (MCCW): paced reaching movements
toward 8 radially displayed targets were presented in a predict-
able counterclockwise order; and 2.Motor sequence learning
(MSEQ): the targets were presented in a repeating pattern.
Subjects were explicitly required to synchronize target acqui-
sition with the tone, thus encouraging sequence learning and
anticipation of the correct target. Performance was quantified
as a global learning index (GL) defined as the total number of
correct anticipatory movements in each PET trial block. Acti-
vation patterns were compared between groups using SPM99
Movement Disorders, Vol. 17, No. 5, 2002
and network analysis. Results: NM-DYT1 did not differ from
controls in MCCW: spatial and timing errors and motor acti-
vation responses were similar for the two groups. During
MSEQ, learning performance (GL) was reduced in the NM-
DYT1 group (P < 0.01). This was associated with a relative
increase (P 0.01) in the activation of the left prefrontal
cortex (BA 11), right anterior putamen and the lateral cerebel-
lum in the gene carriers. In normal subjects performing MSEQ,
GL is highly correlated with the activity of a specific brain
network involving DLPFC, PMC, and posterior parietal re-
gions. However in NM-DYT1 carriers, learning performance
did not correlate (R2 0.09, P 0.3) with the activity of this
network. By contrast, in these subjects GL correlated signifi-
cantly (R2 0.47, P 0.006) with the activity of a different
network involving the striatum and ventral prefrontal cortex.
Conclusions: In NM-DYT1 carriers, motor sequence learning is
associated with relative activation of brain regions normally
mediating the earliest phases of this process. Abnormal transfer
from frontal to posterior parietal cortical areas may be the basis
for the impairment in learning that was observed in these sub-
jects. [Note: This work was supported by the National Institutes
of Health (RO1 NS 37564) and the Dystonia Medical Research
Foundation.]
Dysfunction of Dopaminergic Pathways in Dystonia
J.S. Perlmutter
Washington University School of Medicine, St. Louis, Missouri,
USA
Multiple neuroimaging studies indicate that dysfunction of
dopaminergic pathways contributes to the pathophysiology of
dystonia. Early structural imaging studies identified lenticular
nuclei and other brain regions as sites of pathology in second-
ary dystonias. Later, imaging studies with positron emission
tomography (PET) and functional magnetic resonance demon-
strated dysfunction in putamen and cortical-basal ganglia cir-
cuits including specific abnormalities of dopaminergic path-
ways. These findings fit well with recent observations of re-
duced cortical inhibition in people with dystonia. Structural
abnormalities have been found in the basal ganglia contralateral
to the symptomatic side in hemidystonic patients. The putamen
has been the most common site of such lesions in secondary
dystonias, and volumetric analyses revealed about a 10% in-
creased volume of putamen in those affected by primary cranial
or hand dystonia. PET measurements of regional cerebral blood
flow or metabolism either at rest or during activation have
provided key insights into the pathophysiology of dystonia.
Resting-state studies have identified abnormal function of pu-
tamen in people with primary and secondary forms of dystonia,
as well as alterations in function at other sites in cortical basal
ganglia motor circuits. Activation studies have identified dys-
function in sensory motor processing in dystonia and alter-
ations in brain activity during motor tasks that may be restored
to normal after dopaminergic drugs. Primary and some second-
ary forms of dystonia may be associated with reduced activity
of presynaptic dopaminergic nigrostriatal neurons, as found
with[18F]fluorodopa (FD) PET. Decreased putamenal uptake of
FD may occur in primary dystonias, but there is normal uptake
in dopa-responsive dystonia despite deficient tyrosine hydrox-
ylase activity. PET measurements of radiolabeled dopaminer-
gic ligands have provided additional insights into the function
of dopaminergic pathways in dystonia. Nonhuman primates
 4th INTERNATIONAL DYSTONIA SYMPOSIUM
treated with intracarotid MPTP developed transient hemidys-
tonia prior to hemiparkinsonism. The dystonic phase corre-
sponded temporally with a decreased striatal dopamine content
(9798%) and a transient decrease in D2-like receptor number
(about 30% decrease) in putamen. Patients with cranial or hand
dystonia also had a similar reduction of binding (29% decrease)
of [18F]spiperone in putamen These findings have now been
replicated in a similar group as well as in those with cervical
dystonia. In summary, there is substantial evidence that dopa-
minergic pathways are implicated in the pathophysiology of
dystonia. PET measures of dopaminergic receptor binding in
people with dystonia and in an animal model with transient
dystonia suggest that this involvement may preferentially affect
D2-mediated pathways, which implicates the indirect pathway
of the basal ganglia motor circuit. One primary function of
indirect pathway may be to broadly inhibit unwanted move-
ment during an intended movement. Conceivably, signal pro-
cessing through the indirect pathway could be influenced at
many different points. Regardless of the site of primary pathol-
ogy, we hypothesize that dysfunction of the indirect pathway
could lead to the loss of lateral cortical inhibition and abnormal
central sensory processing. The normalization of the vibration-
induced blood flow response in the dopa-responsive dystonia is
suggestive, but not proof, of this notion. Additional studies
measuring the function of the direct pathway through the basal
ganglia will help clarify its role. Development and application
of new imaging tools may help address these unsettled issues,
providing new insights into the pathophysiology of dystonia.
Functional Anatomy and Pharmacology of Animal Models
of Dystonia
A.R. Crossman
Division of Neuroscience, School of Biological Sciences, Uni-
versity of Manchester, Manchester, and Motac Neuroscience
Ltd., Manchester, United Kingdom
In Parkinsons disease, treatment with levodopa (L-dopa) or
dopamine agonists leads to the development of abnormal in-
voluntary movements (dyskinesias), of which dystonia may be
a major component. In fact, L-dopainduced dystonia remains
to date the only form of dystonia that can be induced in animals
by replicating the known cause in man. There is good evidence
that the fundamental neural mechanisms underlying L-dopa
induced dystonia are the same in other forms of dystonia. Thus,
new treatments for L-dopainduced dystonia are likely to be
beneficial not only in that condition but also in other manifes-
tations of dystonia. There is strong evidence that the neural
mechanisms underlying L-dopainduced, and other forms of,
dystonia involve abnormal patterns of activity in the efferent
neurones of the striatum. These inhibitory, GABAergic, neu-
rones control the output of the basal ganglia, namely the medial
segment of the globus pallidus (GPm) and the substantia nigra,
pars reticulata (SNr). There are two principle types of striatal
efferents. The so-called direct pathway projects directly to
GPm and SNr output neurones. The indirect pathway con-
trols basal ganglia output via the intermediary of the lateral
segment of the globus pallidus (GPl), which in turn inhibits the
subthalamic nucleus (STN). The STN is the major excitatory
drive to basal ganglia output neurones. Evidence suggests that
L-dopainduced dystonia is associated with overactivity of the
direct striatal efferent pathway to GPm and underactivity of the
projection to GPl. Both of these induce abnormal underactivity
1133
of basal ganglia output. Multiple chemical signals and receptors
mediate or modulate the interconnecting pathways by which
these abnormalities are mediated. They, thus, represent poten-
tial targets for therapeutic manipulation. In primate models, we
have demonstrated that L-dopainduced dystonia can be alle-
viated by administration of: (1) -opioid receptor antagonists;
(2) histamine H3 receptor agonists; (3) 2 adrenergic receptor
antagonists; (4) cannabinoid receptor antagonists; and (5)
-opioid receptor antagonists. A key component of the neural
mechanism underlying L-dopainduced dystonia is enhanced
synthesis of the opioid precursor preproenkephalin B (PPE-B)
by the direct striatal output pathway. It is proposed that en-
hanced stimulation of opioid receptors by the products of
PPE-B is responsible for the generation of dystonia. Indeed, in
monkeys with dystonia, there is a down-regulation of opioid
receptors in the output regions of the basal ganglia suggesting
enhanced receptor stimulation. In the MPTP-lesioned primate,
opioid receptor antagonists alleviate L-dopainduced dysto-
nia. Histamine H3 receptor agonists: A key component of the
neural mechanism underlying dystonia is enhanced GABAer-
gic inhibition of basal ganglia outputs by the direct pathway.
H3 receptor stimulation can reduce GABA release in these
structures. H3 receptor stimulation alleviates L-dopainduced
dystonia in MPTP-lesioned monkeys. Alpha 2 adrenergic re-
ceptor antagonists: As outlined above, a key component of the
neural mechanism underlying dystonia is enhanced transmis-
sion in the direct pathway. Alpha 2 adrenergic receptors appear
to play a key role in determining the sensitivity of the direct
pathway to modulation by other transmitter systems, e.g. do-
paminergic, opioid, glutamatergic. We have shown that block-
ade of 2 adrenergic receptors alleviates L-dopainduced hy-
perlocomotion, induced by stimulation of the direct pathway, in
rats and both chorea and dystonia, in MPTP-lesioned monkeys.
Cannabinoid receptor antagonists: The globus pallidus contains
the highest levels of endogenous cannabinoids and cannabinoid
CB1 receptors of any brain region. We have shown that CB1
receptor stimulation can enhance GABA transmission by re-
ducing GABA uptake in basal ganglia output regions. We have
also shown that L-dopainduced dystonia is reduced by the
CB1 antagonist SR141716A in MPTP-lesioned monkeys.
V. MUSICIANS, AND OTHER FOCAL DYSTONIAS
Focal Task-Specific Dystonia in Musicians
S. Frucht
The Neurological Institute, Columbia-Presbyterian Medical
Center, New York, New York, USA
Between 5 and 10% of patients seen at performing arts medi-
cine clinics are afflicted with focal task-specific dystonia,
(FTSD), although the true incidence and prevalence of the con-
dition are unknown. FTSD has been reported in string (violin,
viola, cello), keyboard (piano, accordion, organ, harpsichord),
plectrum (guitar, banjo, lute, mandolin), woodwind (flute, clari-
net, saxophone, oboe, bassoon) and brass players (trumpet,
French horn, trombone and tuba). Symptoms usually begin in
the fourth decade, and a family history of dystonia is absent.
Injury and over-use may be associated with the onset of dys-
tonia, although the role of peripheral trauma as a trigger is
unclear. Among musicians, the hand that performs the more
Movement Disorders, Vol. 17, No. 5, 2002
1134 4th INTERNATIONAL DYSTONIA SYMPOSIUM
complex task is more likely to develop FTSD. Of 129 musi-
cians reported in the literature with FTSD, the right hand was
affected in 64%. Among keyboard players, 75% involved the
right hand (n 61), and plectrum instruments had a similar
predisposition for the right hand (79%, n 19). Among string
players (violin, viola and cello) the situation is reversed, with
71% of reported patients (n 24) affected on the left. Al-
though the numbers are small, published examples of flutists
and clarinetists with FTSD (n 25) support this hypothesis,
with 44% involving the left hand and 54% the right. An in-
creasing number of patients with FTSD of the embouchure
have been recognized. The embouchure refers to the pattern of
muscles of the lower face, tongue and jaw used to control the
force and direction of airflow into the mouthpiece of a wood-
wind or brass instrument. Symptoms began in the fourth de-
cade, often in one particular register or technique, and were
usually insidious and painless. Patients can be categorized into
one of four groups by the phenomenology of their movements:
embouchure tremor, lip-pulling, lip-lock and jaw involvement.
Writers cramp was present in 10% of these patients, and in 5
patients (all involving the jaw), dystonia spread to other oral
tasks such as eating or speaking. The diagnosis of FTSD carries
profound psychological and financial implications, and therapy
of FTSD is of little use to a performing artist unless it produces
virtually 100% recovery. To address these needs, the program
entity Musicians with Dystonia was founded in January of 2000
to offer practical support to musicians afflicted with dystonia,
to raise awareness of dystonia in the musical community and in
the community at large, and to facilitate research collaborations
into the cause and treatment of focal dystonia in musicians.
Brain Mapping in Musicians Dystonia
M.E. Charness1 and G. Schlaug2
1 patients. Almost half of the patients (48 %) with musicians
Department of Neurology, Harvard Medical School, Depart-
ment of Neurology, Brigham and Womens Hospital, Neurol-
ogy Service, VA Boston Healthcare System, Boston, Massachu-
setts; 2Department of Neurology, Harvard Medical School,
Beth Israel Deaconess Medical Center, Boston, Massachusetts,
USA
Task-specific focal dystonia (TSFD) in musicians is a dis-
order of skill. The acquisition of skill in musicians may lead to
adaptive changes in brain function and structure, particularly in
those musicians whose training begins at an early age. Neural
reorganization may result from learning itself, from the repeti-
tive movements involved in practice, or as direct or indirect
consequence of soft tissue and peripheral nerve injuries that
may accompany excessive practice. This neural plasticity may
predispose to the development of TSFD in susceptible musi-
cians. It is unknown what additional factors determine the sus-
ceptibility to develop TSFD; conceivably, genes that govern
brain physiology play a role. Musicians with TSFD show ab-
normalities in sensory processing and sensorimotor integration.
There is fusion, distortion, and rearrangement of the cortical
sensory representation of the digits in musicians with TSFD. In
many instances, neurophysiological abnormalities are observed
bilaterally in patients with unilateral TSFD. It is unclear wheth-
er these abnormalities precede or follow the onset of TSFD.
Dystonic performance in guitarists is associated with reduced
activation of the premotor area and increased activation of the
primary sensorimotor cortex compared to performance in nor-
Movement Disorders, Vol. 17, No. 5, 2002
mal guitarists. Paced, nondystonic tapping of the fifth digit in
normal pianists causes increased activation of the dorsolateral
precentral gyrus and reduced activation of the supplementary
motor area (SMA) and parietal regions compared with non-
musicians. Paced, nondystonic tapping in pianists with TSFD
was associated with increased activation of SMA and parietal
regions, consistent with a reversion of the activation pattern
typically seen in skilled musicians back to the activation pattern
of non-musicians. These studies identify clear differences in the
pattern of brain activation for both dystonic and nondystonic
movements in musicians with TSFD compared with normal
musician controls.
Therapy of Musicians Dystonia
E. Altenmller, H-C. Jabusch, V. Lim
Institute of Music Physiology and Musicians Medicine, Han-
nover University for Music and Drama, Hannover, Germany
Musicians dystonia is a task-specific movement disorder
with an unclear etiology. In order to illuminate epidemiology
and long-term development, follow-up data from 143 patients
diagnosed with musicians dystonia between 1994 and 2000
were analyzed. The minimum follow-up period was 6 months.
Questionnaires and standardized telephone interviews were
used for data collection. Long-term development was recorded
by means of self-assessment. Musicians dystonia occurred pre-
dominantly in males (81 %), and mainly in classical musicians
(93 %). The mean age of onset was 33.4 9.0 years, and in 80
% of the patients the onset occurred before 40 years of age.
Five percent of the patients had at least one first-degree relative
suffering from focal dystonia. A history of pain in the affected
limb prior to the onset of dystonia was found in 9 % of the
dystonia were pianists or guitarists and 51 % had professional
positions as soloists. Localization of dystonia was dependent on
the instrument: 75 % of the diagnosed keyboard instrumental-
ists had right hand dystonia, in 10 % both hands were affected.
86 % of patients with plucking instruments showed right hand
dystonia. In contrast, string players displayed predominantly
left hand dystonia (64 %). In wind players, the disorder oc-
curred as embouchure dystonia in 88 % of brass players and in
13 % of woodwind players. In woodwind players, the right
hand was affected in 35 %, the left hand in 41 %, both hands
in 11 %. In general, localization of dystonia was dependent on
work load and complexity of motor tasks. Patients underwent a
variety of treatments such as monotherapies or combination
therapies with Botox-injections (51 %), Trihexiphenidyl (50
%), pedagogical retraining therapies (15 %), and ergonomic
changes (36 %). In 12 % treatment was not possible or was
refused. 53 % of all patients reported an improvement in the
condition, 2 patients (1 %) reported complete alleviation of
symptoms. 35 % showed no change in symptoms, and in 11 %
symptoms worsened. Concerning their professional activities,
31 % of the patients had the same number of performances as
before onset of dystonia and 4 % performed more often. 36 %
had less performances and 29 % changed their profession. An
objective and comparative evaluation of the different treatment
options requires further studies employing objective measure-
ments of therapeutic progress in musicians dystonia.
 4th INTERNATIONAL DYSTONIA SYMPOSIUM
Limb Immobilization for Occupational Dystonia
A. Priori, A. Pesenti, S. Barbieri
Dipartimento di Scienze Neurologiche, IRCCS Ospedale Mag-
giore di Milano, Milan, Italy
Because current treatments including botulinum toxin or
drugs often yield disappointing results, focal occupational dys-
tonia is a challenging issue in neurological practice, especially
in certain professional categories such as musicians. Though
not a life-threatening disorder, it can severely impair a patients
social life and destroy a professional career. Interestingly,
whereas in patients with focal dystonia the motor area of the
cerebral cortex is enlarged and hyperexcitable, in subjects un-
dergoing prolonged a limb immobilization the cortical repre-
sentation of the immobilized muscles shrinks and are hypoex-
citable. We therefore decided to test the effect of limb immo-
bilization in patients with focal dystonia. In a preliminary open
study in 8 patients we found that after 4 to 5 weeks of limb
immobilization, the benefit of therapy on dystonia varied: in 4
patients we obtained a good improvement, in 3 a mild improve-
ment and in 1 no consistent improvement. Hence, we proposed
immobilization as a possible alternative therapeutic approach to
focal dystonia in selected patients. Despite these extremely
encouraging results, the variability of our patients responses
was large. Unfortunately the sample size was too small for us
to try to identify the clinical profile of the best candidate for
immobilization therapy. After our preliminary open study we
immobilized a considerably larger number of patients, and still
confirmed the variability of the results ranging from marked
improvement, to no improvement at all. With this larger sample
size we tried to find out a posteriori whether patients whose
dystonia markedly improved had some common features. Our
current data suggest that several clinical variables can identify
patients who will benefit most from limb immobilization. So
far the most reliable seem to be a young age (<3537 years); a
short disease duration (<1 year from onset of the first symp-
tom); an onset related to overuse; transient improvement after
a fatiguing contraction (the hand-grip test); and, possibly, no
previous treatment with botulinum toxin. Patients who fulfill all
these criteria should obtain a consistent and marked improve-
ment in their focal occupational limb dystonia. Conversely, in
our experience, in patients without the foregoing criteria im-
mobilization generally fails.
A Review of 111 Musicians with Focal Dystonia Seen at a
Performing Artists Clinic 1985-2002
A.G. Brandfonbrener and C. Robson
Rehabilitation Institute of Chicago, Northwestern University
Medical School, Chicago, Illinois, USA
Although among musicians as a whole focal dystonias are
uncommon, in a specialized clinic serving musicians focal dys-
tonias are seen with greater frequency. We report on a group of
111 musicians diagnosed with dystonia (total instrumentalist
patients, 2330) at the Medical Program for Performing Artists
in Chicago between 1985 and 2002. Excluded were 19 patients
whose symptoms were compatible with dystonia, but were suf-
ficiently atypical to raise questions about the diagnosis. The
demographics of these patients are similar to those reported by
others. Seventy-four percent are men, and 77% are professional
1135
musicians. The age at presentation to the clinic peaked in the
fourth decade of life (45%), and the rest distributed according
to age in a bell-shaped curve. Forty-four percent were seen
during the first year they became aware of symptoms, while
another 20% were seen 5 years or more after the onset. Among
those with hand dystonias are 34 keyboard players, 15 bowed
and 19 plucked string players, 25 woodwinds, and 5 percus-
sionists. All 13 brass players seen have dystonias affecting the
embouchure muscles as do 3 of the flute players. Among key-
boardists 75% had symptoms in their right hands. One of these
has evidence of left involvement as well, 2 years after presen-
tation with the right hand. Among bowed strings 60% have left
hand symptoms, while 95% of plucked strings have right hand
symptoms. Among the woodwinds with hand dystonias, 64%
have left hand symptoms. There are only 5 percussionists, who
were divided 3:2 right versus left hand involvement. Patients
were asked about possible precipitants, including trauma,
changes of technique or instrument, and stress. In 67% no cause
could be clearly identified. Family history of neurological ill-
ness was mostly negative, although the father of 1 patient had
spasmodic torticollis. Included in this report are 1 from each of
2 sets of identical male twins, 1 pair being pianists, the other
violists. All are professionals, trained by the same teachers.
Thusfar only 1 twin of each set is known to be affected with
dystonia. Telephone contact was attempted with all patients not
seen within the past year. Fifty-one were contacted. For 14
patients it was 12 or more years since their initial visit. Thirty-
three of these were professional musicians, of whom 14 are still
playing, albeit with changes in technique and/or repertoire. In
none have the symptoms resolved. Seventeen of the profession-
als no longer play. One patient is deceased, 1 has Alzheimers.
Several who had been primarily performers and others who had
already been primarily teachers, continue teaching. Nine pro
fessional musicians changed careers, 2 others retired. A variety of
treatments were used, none of which were felt to be of significant
help. Only 2 patients had tried Botox. Continued research into
more effective treatments is essential, but of greater priority is
understanding the etiology(ies) of focal dystonias in musicians so
that there can be effective prevention strategies.
The Impact of Focal Dystonia on the Working Life of Mu-
sicians Within the United Kingdom
A.G. Butler
Action for Dystonia, Diagnosis, Education and Research,
Middleton St. George, Co. Durham, United Kingdom
Although something is known about the prevalence of dys-
tonia in general, there was originally little reliable evidence
about the incidence of individual types of dystonia within mu-
sicians. However, during the Epidemiological Survey of Dys-
tonia (ESD) carried out in Northeast England for over 8 years
(since May 1993), a small number of musicians were identified
with different forms of focal dystonia. The primary author, an
ex-professional musician himself, had the opportunity to ad-
dress a conference held in York in England in March 1997,
which was organised by the British Association of Performing
Arts Medicine. By the time of this conference, the author al-
ready had a good idea of the sense of isolation felt by most
people with dystonia had never been previously measured and
as the disorder is predominantly visual in presentation, a num-
Movement Disorders, Vol. 17, No. 5, 2002
1136 4th INTERNATIONAL DYSTONIA SYMPOSIUM
ber of sufferers felt severe social and psychological pressure to
remain hidden from public view. Social isolation in patients
breeds a lack of diagnostic skill in General Practitioners, which
in turn leads to non or misdiagnosis and thus increases the
isolation felt by most sufferers. Therefore the onset of dystonia
for a musician can have a particularly debilitating effect, espe-
cially if that musician develops a focal dystonia affecting the
hands or the neck. We describe briefly the ESD classification of
primary and secondary dystonia and gives the overall preva-
lence figures for the various disorders and relates both sets of
data to the musicians involved in the study. The 5 case histories
involve a professional rock guitarist, a semi-professional club
guitarist and singer, an amateur classical pianist, a world re-
nowned accordion player, and an ex-professional lead singer
with an internationally acclaimed vocal quartet. These musi-
cians show how the onset of dystonia has affected the working
(playing) life of each musician, together with the results and the
effectiveness of Botulinum Toxin therapy in the treatment of
primary focal dystonia of the hands or neck in musicians. Each
case history will show how the onset of dystonia has affected
the working life of each musician. Each case history will have
four sections: 1) the chronological advance of the disorder, 2)
how this affected their playing, 3) any successful treatments,
and 4) the psychological impact of the disorder on the sub-
ject. The impact of focal dystonia makes no distinction be-
tween primary and secondary dystonia because an abnormal
posture or involuntary muscle spasm presents in exactly the
same way in both cases. If the subject becomes unemployed,
due to their dystonia, it does not matter if it was induced,
genetically inherited or idiopathicthey are still economically
vulnerable.
Psychological conditions in musicians with focal dystonia
and those suffering from chronic pain syndromes
H.C. Jabusch,1 S.V. Mueller,2 V.K. Lim,1,3 E. Altenmueller1
1
Hannover University for Music and Drama, Hannover, Ger-
many; 2Otto-von-Guericke-University, Magdeburg, Germany;
3
University of Melbourne, Melbourne, Australia
Focal dystonia in musicians is considered to be a task-
specific movement disorder which may be of different origins.
Although certain psychological characteristics seem to be pre-
dominant in dystonic patients, the role of psychogenesis in the
etiology of focal dystonia remains unclear. Psychological con-
ditions were examined in musicians suffering from focal dys-
tonia (n 20) and compared with those of musicians with
chronic pain syndromes (n 20) and healthy musicians (n
30). Participants were investigated by means of self-estimation
using the revised version of the Freiburg Personality Inventory
(FPI-R), a German multidimensional personality inventory, as
well as the Questionnaire for Competence and Control Orien-
tations. An additional questionnaire was developed focusing on
perfectionistic tendencies and anxiety disorders. There were
significant differences in the psychological conditions of dys-
tonic musicians compared to healthy musicians. In particular, a
pattern of anxiety disorders and highly perfectionistic tenden-
cies was seen in dystonic individuals. A retrospective inquiry
revealed that anxiety and perfectionism had already been pre-
sent before onset of focal dystonia, hence these conditions
Movement Disorders, Vol. 17, No. 5, 2002
could not be interpreted as psychoreactive. Comparing both
patient groups, an overlap was seen in some anxiety subscales
as well as in the health concern subscale and somatic com-
plaints subscale of the FPI-R. The findings support the assump-
tion that certain psychological conditions such as perfectionism
and anxiety disorders can play a crucial role in the progress of
musicians disorders such as focal dystonia and chronic pain
syndromes. It is possible that these psychological conditions
may also be triggering factors in the etiology of focal dystonia
in musicians. It is necessary to discuss whether the above men-
tioned psychological patterns and attitudes should be addressed
in the education of musicians with the particular aim of pre-
vention of movement disorders.
Focal Dystonia in Violin and Viola Instrumentalists
S.U. Schuele and R.J. Lederman
Department of Neurology and Medical Center for Performing
Artists, Cleveland Clinic Foundation, Cleveland, Ohio, USA
Background: Occupational cramp in musicians has been
recognised for 150 years, but only in the past two decades there
has been a resurgence of interest in this problem. Despite its
overall rarity, the diagnosis of focal dystonia is made in a
substantial number of instrumental musicians seeking care for
playing-related problems, ranging from 8 to 14% in two larger
series. Methods: We present 22 string instrumentalists (16 vio-
lin, 6 viola players) seen at the Cleveland Clinic Foundation
between 1987 and 2001 who were diagnosed with focal dys-
tonia at initial presentation. Of the 22, 17 were professional
musicians, 2 were mainly teachers, and 3 were music students
(18 men, 4 women; mean age at onset, 33 years; range, 2268
years; mean duration of symptoms on presentation, 4.7 years).
Results: Main complaints were loss of control and/or involun-
tary movements affecting one or several fingers of the finger-
ing hand in 16 patients, the bow arm in 5, and the neck in
1 patient. In all patients the symptoms could be confirmed by
watching them play their instrument. Eleven musicians had an
EMG study, and results were abnormal in 4 of them. Two of
these 4 patients underwent surgery for entrapment neuropathy
without significant or lasting improvement. We conducted a
telephone survey with a standardized questionnaire. Follow-up
information was obtained in 19 out of 22 musicians (mean
follow-up time, 10.2 years; 14.9 years after onset of symp-
toms). Treatment attempts included physical therapy, retrain-
ing, and medication (in most cases trihexyphenidyl). In selected
patients we also offered Botox injections or splint devices.
For all these options the response varied between none and
mild to moderate improvement. 3 patients reached their previ-
ous level of performance: 2 by altering their technique and
refingering, the third one, with isolated dystonia of one distal
finger, had an excellent recovery after surgical immobilization
of his distal finger joint. Overall, only 6 out of the 19 musicians
were able to stay in their professional careers, the majority
either became instrument teachers or entirely changed their
professional field. Conclusions: Focal dystonia may affect limb
muscles in violin and viola instrumentalists, often early in their
professional career. Currently available therapy offers mild to
moderate symptom control; more effective approaches are
badly needed.
 4th INTERNATIONAL DYSTONIA SYMPOSIUM
Abnormal SensoryMotor Processing of Musicians with
Focal Dystonia.
V.K. Lim,1,3 J.L. Bradshaw,2 E. Altenmller3
1
University of Melbourne, Melbourne, Australia; 2Monash
University, Monash, Australia; 3Institute of Music Physiology
and Musicians Medicine, Hannover University for Music and
Drama, Hannover, Germany
Musicians regularly perform complex movements with great
temporalspatial accuracy and emotion. In some individuals a
task-specific, painless cramping or incoordination of the fingers
and hands occurs. This musicians dystonia affects integration
of the sensorimotor system at multiple levels. Contingent nega-
tive variation (CNV) is an important paradigm for musicians as
it involves a complex interaction between incoming sensory
input, motor output and expectations, and is also highly con-
textual. The CNV can be elicited in both movement and non-
movement conditions. Therefore, the CNV and electromyog-
raphy (EMG) were recorded in order to investigate sensorimo-
tor integration in musicians with focal dystonia. In this study, 7
male professional pianists presented dystonic flexion symp-
toms primarily in the ring and small fingers whilst playing the
piano. They were compared to control participants who were
matched for age and professional music ability. Tactile stimuli
(plastic rods, contact surface of 1 mm) were presented with a
force of 8.21 1.51 Newtons to the fingernail of the small
finger. The task employed a simple reaction time paradigm; the
participants were given 448 pairs of mechanical warning (S1)
and imperative (S2) stimuli. S1 predicted 75% of the trials
where S2 would arrive (valid). The other 25% of the trials, S2
occurred opposite to S1 (invalid). All trials were randomly
presented. Immediately upon presentation of the imperative
stimuli, participants were required to press a button with their
small finger. In addition to the movement experiment, a control
condition with 224 pairs of trials without movement was con-
ducted (presentation of the two experiments were counterbal-
anced). The participants were not required to move; however
they had to count the number of double stimulations that
occurred 25% of the time. Attentional and motivational effects
were minimised by subtracting the Non-movement amplitudes
from the Movement tasks. This allowed a direct comparison of
the motor component separate from other aspects of the
CNV. There were no significant differences in the amplitudes
of the early CNV (750850 msec). In contrast, for the late CNV
(19002000 msec), patients had significantly increased CNV
amplitudes (5.04 mV) compared to controls (1.34 mV).
There were no significant differences in the affected and unaf-
fected hands in either early or late CNV, and no significant
EMG differences. Similarly, there was also no significant
group CNV difference between valid and invalid trials (cuing).
Central electrodes produced significantly greater amplitudes
than other sites. While the CNV data did not show a cuing
effect; reaction time data showed an effect. There was no group
difference in the unaffected hand; however, there was a sig-
nificant group interaction in the affected hand with cuing. Cu-
ing had a greater affect on the performance of controls than
patients. Valid responses were faster than invalid trials. Con-
trols were also slower than patients in both types of trials (valid
and invalid). The results suggest that pianists with focal dys-
tonia have normal arousal and processing of the first stimulus
(early CNV). However, the pianists with focal dystonia com-
pared with controls have abnormal inhibition and excitatory
networks for motor preparation and sensory integration as re-
1137
flected in the late CNV amplitudes and between movement and
non-movement experiments.
Altered Movement Related Cortical Potentials in Musi-
cians Focal Dystonia when Performing Skilled Movements
with the Affected and Unaffected Hand
T. Peschel,1,2 E. Altenmller1
1
Hannover University for Music and Drama, Hannover; 2Han-
nover Medical University, Hannover, Germany
Musicians focal dystonia (FD) is characterised by a painless
loss of muscular control in highly practiced skilled movements
occurring only in a relevant context. The increased prevalence
of FD in musicians compared to other occupational cramps
may be related to the specific qualities of their sensorimotor
skills. In addition, the extensive repetitive use of the hand for
years may lead to long term practice-dependent plastic changes
in cortical sensorimotor representations. Movement related cor-
tical potentials (MRCPs) reflect the sequential activation of the
sensorimotor cortical areas involved in the planning and ex-
ecution of voluntary movements. In this study, MRCPs were
investigated in a relevant task-specific condition using a grand
piano. Nine right-handed musicians suffering from FD were
compared to an age-matched group of musicians playing the
same instrument and to a group of non-musician controls. MR-
CPs were recorded separately for each hand from 11 electrode
locations placed over the sensorimotor cortex. Additionally,
EMG of the flexor digitorum superficialis and a trigger signal
from a prepared Steinway grand piano key were recorded. Sub-
jects had to play (1) a single note depressing the key with the
index finger, and (2) a complex pianistic sequence which in-
duced dystonic symptoms in the patient group and was also
playable for non-musicians. All tasks were to be executed on
the grand piano, producing a natural feeling for touch as well as
sensory and auditory feedback. Musicians compared to non-
musicians showed higher premovement activity and a reduced
motor potential especially when performing the complex task.
The activation pattern in the patients depended on the perform-
ing hand. Compared to musician controls using the non-
affected hand, they exhibited reduced premovement and motor
activity whereas task performance of the dystonic hand was
characterised by higher premovement potentials especially of
the late component 500 to 100 msec prior to movement onset.
This abnormal activation pattern was also present during a
simple key stroke which did not induce dystonic symptoms in
the patients. The study suggests that repetitive skilled finger
movements may lead to functional changes in cortical activa-
tion pattern which are most prominent during movement prepa-
ration and may reflect use-dependent cortical plasticity in mu-
sicians. Furthermore, our results demonstrate for the first time
that the primary sensorimotor cortex in task-specific focal dys-
tonia, rather then being underactive as indicated by recent
MRCP studies, may be overactive during movement prepara-
tion with the affected hand when tested in a task-specific real-
istic scenario inducing the dystonic movement. The alteration
of MRCPs when using the unaffected hand gives further evi-
dence for a generalized disorder underlying FD. Conclusion:
Higher MRCP amplitudes during movement preparation with
the affected hand reflect either a compensatory mechanism in-
dicating more anticipatory neuronal activity to design the ap-
propriate movement or reflect defective cortical inhibition due
to maladaptive plasticity in musicians dystonia.
Movement Disorders, Vol. 17, No. 5, 2002
1138 4th INTERNATIONAL DYSTONIA SYMPOSIUM
Cognition and Affect in Patients with Cervical Dystonia
and Tremor
K. Vermilion, J. Johnson, D. Duane
Arizona Dystonia Institute/Arizona State University,
Scottsdale, Arizona, USA
Background: Isolating differential characteristics may clarify
the relationship between tremor and cervical dystonia. Family
history of movement disorder and psychiatric states, as well as
personal characteristics of cognition, mood and tremor location
may differ in patients with (idiopathic) essential tremor (ET)
vs. cervical dystonia with tremor (CD/T) versus cervical dys-
tonia without tremor (CDnoT). Objectives: To assess family
history of movement and mood disorder, and personal qualities
of cognition and mood in a referral population of patients with
CD/T. Methods: 79 CD/T patients (87% women; mean age
onset CD, 47 years; mean age onset, T 47 years) were similarly
evaluated at mean age 59 years. Analysis included recalled age
onset CD and T as well as T location; family history of psy-
chiatric and movement disorders; scores on MMPI, Hamilton
Depression and/or Spielberger Anxiety Rating Scales; neuro-
psychological performance on: Rey Auditory Verbal Learning
Test (AVLT), Three Letter Cancellation Task (LCT), Digit
Span (DS), Rey-Osterrieth Complex Figure Test (ROCFT),
Conners Continuous Performance Test (CPT), Test of Vari-
ables of Attention (TOVA), Wisconsin Card Sorting Test
(WCST). Results: Family history anxiety 10 (13%) depression
17 (22%; OCD 5, psychosis 4, alcoholism 29); non-PD tremor
38 (48%; head only 13, hands only 17, both head & hands 8),
dystonia 13 (17%), scoliosis 11 (14%), PD 6 (8%). Personal
evidence anxiety 41 (52%), depression 57 (72%; 7 also OCD).
Neuropsychological studies (age adjusted): Impaired AVLT
9/72 (13%), Impaired verbal memory 6 of 72 (8%), Impaired
auditory digital memory 4 of 41 (10%), Impaired visual vigi-
lance (LCT) 46 of 72 (64%), Impaired visuomotor skills 1 of 68
(1%), Impaired visual memory 11 of 68 (16%), Impaired visual
attention (TOVA/CPT) 13 of 14 (93%), Impaired executive
function (WCST) 12 of 21 (57%). Conclusions: As we have
shown elsewhere, like patients with ET (Vermilion, Stone, Du-
ane, 2001), CD/T patients have a high frequency of family
history of psychiatric disorder more apt to be depression than
anxiety but both are prevalent as they are in the patients them-
selves. Similarly, family history of tremor is prevalent in both
ET and CD/T, but a greater likelihood that tremor in relatives
is of the head in CD/T and of the hands more than head in ET,
as it is in the affected patients themselves. In patients, psychi-
atric comorbidity is high in CD/T, especially with respect to de-
pression, whether due to pain and distorted self-image or biologi-
cal is unclear. Cognitive impairment is greatest in tasks requiring
attention, whether secondary to distraction from the movement
disorder or secondary to basal ganglion to frontal cortex dysfunc-
tion is also unclear but is similar to that observed in ET.
Clinical Features of the Geste Antagoniste in Cervical Dystonia
S.R. Filipovic,2 M. Jahanshahi,1 R.Viswanathan,1 P. Hey-
wood,3 K.P. Bhatia,1 D. Rogers2,3
1
Institute of Neurology, London; 2Burden Neurological Insti-
tute, Bristol; 3Frenchay Hospital, Bristol, United Kingdom
A unique feature of dystonia is that patients are often able to
reduce/eliminate the abnormal posture using certain manoeu-
Movement Disorders, Vol. 17, No. 5, 2002
vres that involve tactile or proprioceptive stimulation. Although
widely recognised, these manoeuvres or gestes antagonistes
(GA), have not been systematically analysed. To assess this
phenomenon in more detail, we developed and administered a
questionnaire to 94 successive patients with idiopathic cervical
dystonia (CD) attending two botulinum toxin clinics (London
and Bristol). Sixty patients (63.9%) reported a GA. There were
no differences between patients with and without a GA in terms
of age (55.2 12.5 years vs. 58.1 10.0 years), sex (women
63.3% vs. 61.8%), duration of disease (median 13 vs. 11 years),
age at onset (median 43 vs. 46 years). Patients with or without
a GA reported similar levels of control over their head/neck/
shoulder position (median 5, on 010 scale). In both groups,
torticollis was the most common (91.7% vs. 87.9%), while
laterocollis (41.7% vs. 45.5%) and anterocollis/retrocollis
(25.0% vs. 30.3%) were less frequent. A sizeable proportion of
patients in both groups reported head tremor (56.7% vs.
66.7%). Among those with a GA, 58.3% of patients discovered
their GA within the year of CD onset, while 35.0% discovered
it later (median 5 years). Additional 6.7% of the patients de-
tected a GA while completing the questionnaire. In the majority
(91.2%) the GA was still effective. The GA target spots were
mostly located on the cheek (53.3% ) and chin (43.3%), back of
the neck (45.0%) and head (35.0%). Most patients (86.7%)
reported that the GA effect is dependant on the part of the hand
used to touch face/head/neck. The index (59.6%) and middle
(48.1%) fingers and the palm (40.4%) were the most used. The
40.0% of the patients described the contact between the hand
and the face/head/neck as light touch, while 60% described it
as push or pull. Touching the GA target spot with an object
(other than the patients hand) was effective for 26.8%, while
merely thinking of performing the GA was effective for 15.3%.
Other people were able to elicit the effect by touching the GA
target in 27.1% of patients. Most (86.0%) felt that the GA effect
on CD starts either as soon as (42.1%) or shortly after
(43.9%) touching the GA target spot, and lasted as long as the
spot is touched (87.9%). Interestingly, 7 patients (12.3%) re-
ported that the effect on CD starts as soon as hand begins
moving towards GA target spot. The majority (83.9%) re-
ported that the GA improves their CD by 50%, while almost
one third (30.4%) felt that the GA improves their CD greatly
(i.e., >75%) or completely. The GA effect was judged to be
slightly better for improving head/neck/shoulder position than
for changing neck and shoulder movements and pain. The al-
most ubiquitous presence and remarkable efficacy of the GA in
CD warrants further investigation of its physiology which may
provide clues for understanding the neurobiology of dystonia
and open new avenues for its treatment.
VI. THERAPEUTICS
Dystonia: Medical Therapy and Botulinum Toxin
J. Jankovic
Baylor College of Medicine, Houston, Texas, USA
The symptomatic treatment of dystonia has markedly im-
proved, particularly since the introduction of botulinum toxin
(BTX) and as a result of advances in stereotactic surgery. The
selection of a particular choice of therapy is largely guided by
 4th INTERNATIONAL DYSTONIA SYMPOSIUM
the severity of the symptoms, data based on clinical trials,
etiology of the dystonia, and by personal clinical experience.
Because dopa-responsive dystonia may not be easily differen-
tiated from primary dystonia (e.g., DYT1) and is often misdi-
agnosed as cerebral palsy, a therapeutic trial of levodopa should
be considered in all patients with childhood-onset dystonia.
Unpredictable response and the possibility of undesirable side
effects, particularly sedation, parkinsonism and tardive dyski-
nesia, the use of dopamine receptor blocking drugs in the treat-
ment of dystonia has been essentially abandoned. Dopamine
depleting drugs, however, such as tetrabenazine, have been
found useful in some patients with dystonia, particularly in
those with tardive dystonia. Tetrabenazine has the advantage
over other antidopaminergic drugs in that it does not cause
tardive dyskinesia, although it may cause transient acute dys-
tonic reaction. Anticholinergic medications such as trihexyphe-
nidyl have been found to be most useful in the treatment of
generalized and segmental dystonia. This therapy is generally
well tolerated when the dose is increased slowly. Some patients
require up to 60100 mg a day, but may experience dose-
related drowsiness, confusion, memory difficulty, and halluci-
nations. Benzodiazepines may provide additional benefit for
patients whose response to anticholinergic drugs is unsatisfac-
tory. Oral baclofen, GABAb autoreceptor agonist, may be oc-
casionally helpful in the treatment of dystonia, but continuous
intrathecal infusion of baclofen may be particularly effective in
patients with spastic dystonia affecting the legs and trunk. The
introduction of botulinum toxin (BTX) into clinical practice the
late 1980s revolutionized treatment of dystonia. The most po-
tent biological toxin, BTX blocks the release of acetylcholine at
the neuromuscular junction causing focal chemodenervation
and as such it has become a powerful therapeutic tool in the
treatment of a variety of neurologic, ophthalmic, and other
disorders manifested by abnormal, excessive, or inappropriate
muscle contractions. Previously approved for the treatment of
strabismus, blepharospasm and other facial nerve disorders,
including hemifacial spasm, BTX type A (Botox) and BTX
type B (Myobloc) have been approved by the FDA for the
treatment of cervical dystonia in 2000. The usefulness of BTX
in patients with focal dystonias and other disorders causing
muscle spasms is now well accepted, and BTX has been dem-
onstrated to have a positive effect on health-related quality of
life. Although there is concern about the possibility of immu-
noresistance due to blocking antibodies, we have shown that
the current Botox, used since 1998, has a relatively low risk of
blocking antibodies.
Pallidotomy for Dystonia
B. Ford
Columbia University, New York, New York, USA
The rationale for treating dystonia using pallidotomy or thal-
amotomy, or indeed deep brain stimulation, is Meyers seminal
1942 observation that selectively placed lesions of the basal
ganglia could abolish abnormal involuntary movements with-
out producing weakness. Many different ablative procedures
have been used to treat dystonia over the years. In the last
decade, driven by successful results in treating Parkinsons
disease, advances in neuroimaging, a better understanding of
motor electrophysiology and refinements in neurosurgical tech-
nique, the modern posteroventral medial pallidotomy emerged
as the most effective lesion-based treatment for severe dysto-
1139
nia. Pallidotomy targets the sensorimotor projection from the
globus pallidus to the thalamus. A lesion at this site interrupts
the abnormal neuronal signaling in the pallido-thalamo-cortical
pathway that is the putative electrophysiological substrate for
dystonia and other hyperkinetic disorders. The literature on
pallidotomy for dystonia consists of open-label, retrospective
series that have not used control or comparison groups, confir-
mation of lesion location or long-term follow-up. Despite these
limitations, numerous recent reports and small series describe
the outcome of approximately 75 patients in sufficient detail to
make several observations. Bilateral pallidotomy can reduce
symptoms of dystonia by 30 to 80%, according to dystonia
severity rating scale scores, leading to important improvements
in gait and function. Bilateral pallidotomy is generally required
for bilateral or axial symptoms. Primary dystonia seems to
respond better than secondary dystonia. The reduction in dys-
tonia following pallidotomy is not necessarily acute but can be
delayed and progressive, suggesting a gradual restoration of
normal signaling in the pallido-thalamo-cortical network. But
despite its advantages over all previous lesion-based ap-
proaches for dystonia, pallidotomy seems destined to be re-
placed by GPi deep brain stimulation, a technique that in its
earliest application appears to be more effective and safer.
Pallidal Stimulation for Dystonia
A.M. Lozano and A. Abosch
Division of Neurosurgery, Toronto Western Hospital, Toronto,
Ontario, Canada
The net output of the basal ganglia is tightly regulated by the
activity and balance of driving and inhibitory circuitry. In
pathological states, disrupted activity in the main outflow
nucleus, the internal segment of the globus pallidus (GPi) is
relayed to the motor areas of the thalamus and brainstem. The
behaviour of these targets receiving this disrupted outflow, is
consequently also disrupted which in turn produces the pro-
found disturbances in motor function that are characteristic of
parkinsonian states and certain forms of dystonia. Therapeutic
efforts are directed at reversing or canceling the pathological
basal ganglia output. When drugs are ineffective or have short-
comings, surgical approaches can be considered. It is interest-
ing and paradoxical that elimination of this abnormal activity
with destruction of the motor GPi is usually well tolerated and
produces little in the way of overt motor deficit. Indeed having
no motor pallidum (as with pallidotomy) appears to be prefer-
able to having a pallidum generating and transmitting patho-
logical inputs to downstream targets. This observation brings
into question the mysterious role of GPi in normal motor func-
tion. Nevertheless, bilateral pallidal lesions can be associated
with significant adverse effects including speech difficulties
and cognitive disturbances. It is for this reason that neurosur-
geons have sought to develop surgical procedures that offer the
efficacy of selective pallidal lesions but have a better index of
safety. With the introduction of deep brain stimulation (DBS)
to treat first chronic pain and then Parkinsons disease (PD), it
became logical to apply DBS to treat dystonia. There is now
increasing experience in the use of DBS to treat various forms
of dystonia. The initial results suggest that certain primary
dystonias can show a strong improvement with GPi DBS, and
the accumulated reports indicate that pallidotomy and pallidal
stimulation can each be safe and effective treatments for dys-
tonia. However, determination of the optimal surgical treatment
Movement Disorders, Vol. 17, No. 5, 2002
1140 4th INTERNATIONAL DYSTONIA SYMPOSIUM
for dystonia is difficult given the variability in techniques, tar-
gets, underlying pathophysiological mechanisms, the length
and nature of follow-up, the small numbers of patients per
study, and the lack of blinded, prospective trials. It appears that
patients with idiopathic generalized dystonia, particularly those
with DYT1 respond best to pallidal interventions. The response
in secondary dystonias is more variable and reflects the het-
erogeneity in the extent of the lesion and distribution of in-
volvement of neural structures and the accompanying neuro-
logical deficits.
Dystonia: A Model Based on Electrophysiological Record-
ings in the Operating Room.
J.L. Vitek
Emory University, Atlanta, Georgia, USA
Although dystonia has long been considered a hyperkinetic
movement disorder, the evidence to support such a classifica-
tion was based on the presence of excessive involuntary move-
ment, not on physiological data. Only recently, with the return
of surgical procedures using microelectrode guidance for the
treatment of dystonia, has electrophysiological data demon-
strated a decrease in the mean discharge rate of neurons in the
internal segment of the globus pallidus (GPi). In addition to
reductions in mean discharge rates in GPi, examination of
spontaneous neuronal activity in patients with dystonia and
hemiballismus have revealed changes in the pattern, degree of
synchronization and somatosensory responsiveness of neurons
in the pallidum. Contrary to the tonic pattern of discharge pres-
ent in normal animals, spontaneous discharge patterns of neu-
rons in GPi are highly abnormal in patients with dystonia,
occurring in irregularly grouped discharges with intermittent
pauses. Unlike PD, where the mean discharge rate of neurons is
increased in GPi and decreased in GPe and the patterns of
discharge are clearly different, in dystonia the mean rates and
patterns of discharge of GPe and GPi neurons appear very
similar. The most obvious mechanism to explain the rate
changes in GPe and GPi is an increase in the inhibitory output
from the striatum via the direct and indirect pathways. Thus,
one could argue that, at least in primary dystonia, activity in
both the direct and indirect pathways are overactive. Evidence
in support of increased activity in the indirect pathway is de-
rived from the finding of decreased mean discharge rates in
GPe and increased responses of neurons in GPi to passive
manipulation of the limbs. The increased sensory driving in
dystonia, in fact, strongly resembles that which occurs in PD,
where reduced mean discharge rates in GPe leading to in-
creased STN drive on GPi is well established, and is consistent
with studies in primates that suggest proprioceptive input
reaches GPi largely via the STN. The reduced rate of discharge
of GPe would be expected to increase rates in GPi, however,
mean discharge rates in GPi in dystonia are not increased. In
fact, they are decreased. As such, in dystonia excessive inhibi-
tory output from the direct pathway must play a dominant role
in determining the mean discharge rate, while the increased
activity in the indirect pathway accounts for the observed al-
teration in receptive field properties of neurons in GPi. While
increased activity in the direct and indirect pathway can ac-
count for the reduction in mean discharge rate and alteration in
receptive field properties of neurons, changes in the pattern of
neuronal activity in GPi likely plays a key role in the develop-
ment of dystonia as evidenced by the improvement in dystonic
Movement Disorders, Vol. 17, No. 5, 2002
symptoms following pallidotomy or during pallidal deep brain
stimulation. Changes in the pattern of neuronal activity in GPi
could occur as a direct result of transmission of such activity
from the STN, GPe, CM or striatum. They could also occur as
the result of increased inhibitory and excitatory activity to the
GPi from the striatum and STN, respectively. Such changes in
excitatory and inhibitory input to the same structure and/or the
presence of strong temporal fluctuations in synaptic inputs have
been proposed to result in the type of irregularity in neuronal
activity observed in these patients. Thus, in addition to changes
in mean discharge rate, changes in pattern, synchronicity and
responsiveness to somatosensory input are now considered im-
portant features for models of dystonia.
Off-Period Dystonia in Parkinsons Disease But Not Sec-
ondary and Primary Generalized Dystonia Is Improved by
High Frequency Stimulation of the Subthalamic Nucleus
O. Detante,1 P. Krack,1 L. Vercueil,1 S. Chabardes,2 A.L.
Benabid,2 P. Pollak1
1
Neurology Department, Grenoble; 2Neurosurgery Depart-
ment, Grenoble, France
Background: High frequency stimulation of the subthalamic
nucleus (HF-STN) improves off-period dystonia in Parkinsons
disease (PD). As off-period dystonia clinically can mimic gen-
eralized dystonia of other causes, we proposed bilateral HF-
STN stimulation to patients suffering from generalized dysto-
nia. Objective: To compare the efficiency of STN stimulation
on off-period dystonia and generalized dystonia. Methods:
From a larger series, we selected 22 patients with severe pre-
operative off-period dystonia rated greater than 3 in at least one
limb on a severity score ranging from 0 to 4. Four patients with
generalized dystonia (Hallervorden-Spatz disease, n 3; pri-
mary, n1) underwent bilateral HF-STN stimulation. Dystonia
of the four limbs was rated in all patients before surgery and 3
months after surgery. Results: In PD, bilateral HF-STN stimu-
lation reduced the severity of off-period dystonia by 70% on the
4 limbs (preoperative average severity score 2.03 1.49;
postoperative average severity score 0.6 0,78). Bilateral
HF-STN stimulation had no effect on generalized dystonia
(preoperative average severity score 3.25 0.77 ; postop-
erative average severity score 3.12 0.62). Conclusion: In
spite of clinical resemblance between off-period dystonia in
Parkinsons disease and generalized dystonia, the effect of
chronic bilateral HF-STN stimulation was different in these
two pathologies. HF-STN stimulation was highly effective on
off-period dystonia in Parkinsons disease, whereas it did not
improve generalized dystonia. Pathophysiological mechanisms
underlying dystonia in these pathologies are still unknown.
Assuming that HF-STN stimulation inhibits local neuronal ac-
tivity, our findings suggest that they are probably very different
notably for the STN neuronal activity.
Autonomic Side Effects of Botulinum Toxin Type B
Therapy
D. Dressler and R. Benecke
Department of Neurology, Rostock University, Rostock, Ger-
many
Botulinum toxin type A (BTX-A) has been used for many
years for treatment of muscle and exocrine gland hyperactivity
 4th INTERNATIONAL DYSTONIA SYMPOSIUM
disorders. Recently, botulinum toxin type B (BTX-B) became
available for this purpose. When we started clinical use of
BTX-B we noticed a side effect profile not seen with BTX-A
before. Altogether 30 patients were included in this study.
Twenty-four patients suffered from cervical dystonia (CD pa-
tients: 9 women, 15 men; mean age, 52.4 13.2 years; duration
of symptomatology, 11.6 8.0 years). Nine of them received
botulinum toxin for the first time (CD-de novo patients), 15
were treated with BTX-A until formation of antibodies termi-
nated its efficacy (CD-antibody patients). BTX-B therapy of
cervical dystonia was performed with NeuroBloc (11834.7
2039.3 mU; Elan Pharmaceuticals, Shannon, Ireland). Six pa-
tients were treated with BTX-B for focal hyperhidrosis (HH
patients: 4 women, 2 men; mean age, 30.7 11.3 years; dura-
tion of symptomatology, 19.2 10.5 years) with a dose of
5666.7 2658.3 mU. Five of the HH patients received addi-
tional BTX-A (Botox 100 mU; Allergan, Irvine, CA). None of
the patients was currently on anticholinergic medication. In CD
patients side effects included dryness of mouth (total, 21/24;
duration, 4.5 1.93 weeks; severe, 10/24; moderate, 7/24;
mild, 4/24), accommodation difficulties (7/24), conjunctival ir-
ritation (5/24), generalised or focal reduction of sweating (4/
24), heartburn (3/24), swallowing difficulties (3/24), constipa-
tion (3/24), bladder voiding difficulties (1/24), oral and vaginal
soor (1/24), dryness of nasal mucosa (1/24) and head instability
(1/24). In HH patients accommodation difficulties (4/6), dry-
ness of mouth (2/6), conjunctival irritation (1/6) and swallow-
ing difficulties (1/6) were noticed. Patients without dryness of
mouth received NeuroBloc 6742.9 3127.8 mU; patients with
dryness of mouth received 11227.8 2851.9 mU (Mann-
Whitney U test, P < 0.01). Autonomic side effects occur far
more often after BTX-B than after BTX-A and frequently cause
considerable distress. Their localisation suggests systemic
BTX-B spread. Frequency and nature of motor side effects are
similar to BTX-A. Whether BTX-B has a particularly high
affinity to autonomic nerve endings and a particularly low af-
finity to neuromuscular nerve endings or whether the reverse is
true cannot be decided yet.
Treatment of the Patient with Cervical Dystonia: Is Botu-
linum Toxin Enough?
T.T. Warner, Y. Ben-Shlomo, L. Camfield
On behalf of Epidemiological Study of Dystonia in Europe
Collaborative Group, London, United Kingdom
Background: Little is known about the quality of life of
patients with cervical dystonia (CD) and the factors that affect
this. Treatment trials in CD have centred on the use of
observer-dependent physical scales and do not incorporate the
patients perspective. Objective: To examine how CD affects
quality of life. Methods: We studied a cohort of patients from
seven European countries. Cases completed a postal question-
naire which collected data on the SF-36 as the main outcome
and a wide variety of explanatory data. Two hundred and eighty
nine subjects (110 men, 188 women; mean age, 55 years) com-
pleted the questionnaire (75% response rate). Results: Cervical
dystonia had a significant negative impact on quality of life
compared with age-matched general population data. A striking
finding was this negative impact was comparable to other neu-
rological conditions (Multiple sclerosis, Parkinsons disease
and stroke) generally perceived to be of greater clinical sever-
ity. Both physical and mental quality of life scores were pre-
1141
dicted by self-esteem and self deprecation, educational level,
employment status, social support, response to botulinum
toxin, disease severity, social participation, stigma, acceptance
of illness, anxiety and depression. In multivariate analyses, the
strongest predictors were anxiety and depression. Severe de-
pression was association with a 19 point decrement on the
physical summary score (95% CI, 31.7 to 6.6; P 0.003),
although disease duration and severity still remained predictors.
Conclusions: Care of patients with cervical dystonia must not
only focus on reducing the severity of dystonia with physical
techniques. To date psychological aspects have been neglected
and interventions aimed at treating depression and or anxiety,
especially of a cognitive nature, may have a large impact on
improving quality of life.
Dystonia and Headaches: The Response to Botulinum
Toxin (BTx) Therapy
N. Galvez-Jimenez, C. Lampuri, R. Patino-Piccirilo, M.
Hargreave
The Cleveland Clinic Florida, Weston (Fort Lauderdale),
Florida, USA
Headaches, musculoskeletal and other facial pain syndromes
are a frequent complaint in patients with cranio-facio-cervical
dystonias. During routine botulinum toxin (BTX) therapy,
many patients find these symptoms to be improved. To the best
of our knowledge this has not been systematically evaluated.
Our goal was to determine the prevalence, and clinical features
of the different types of headaches (as defined by the IHS) its
relationship with types of cranio-facio-cervical dystonias and
the response to BTX treatment. The movement disorders data-
base was examined and those patients with cranio-facio-
cervical dystonia were identified. Of the 234 patients treated
with BTX between 1996 and 2001, 70 were included in the
study (17 blepharospasm, 8 oromandibular dystonia, 45 cervi-
cal dystonia) with a mean age of 41.85 years (S.D., 14.02).
Interim analysis demonstrated that most patients (62%) had
chronic muscle-tensiontype headache (CMTTH), beginning
during early adulthood in 54%, and later in life in 46%. Fifty-
four percent of CMTTH patients had onset of their headaches
concurrent with the onset of dystonia. Migraine type headaches
(MTH) were noted in 52% of patients and 32% of such patients
related the onset of migraine headaches with the onset of dys-
tonia. A great proportion of patients (78%) had a mixed head-
ache syndrome (CMTTH+MTH). Cervicogenic headache was
found exclusively in some patients with cervical dystonia. Fifty
percent of patients with blepharospasm and oromandibular dys-
tonia had CMTTH but no migraine-type headaches. Using a
visual analog rating scale, 67% of patients rated their head-
ache improved from baseline after botulinum toxin treatment.
Patients with migraine headaches and those with cervical dys-
tonia who have CMTTH found relief with BTx when injected
into the deep cervical paraspinal, trapezius, temporalis and oc-
cipitalis muscles, in addition to the frontalis, procerus, and
corrugator muscles. No ptosis, diplopia, swallowing difficul-
ties, or neck weakness was reported. Most patients complained
of pain at the site of injection. Some patients had a transient
sense of heaviness at the forehead and, at times, transient in-
ability to elevate the eyebrows in those treated for blepharo-
spasm or hemifacial spasm when injected at the forehead
muscles (frontalis, corrugator, and procerus muscle). CMTTH,
followed by MTH, and other types of headaches and muscu-
Movement Disorders, Vol. 17, No. 5, 2002
1142 4th INTERNATIONAL DYSTONIA SYMPOSIUM
loskeletal pain syndromes appear to be common concurrent
complaints in patients with cranio-facio-cervical dystonias.
BTX therapy appears to be effective as migraine and CMTTH
preventive treatment in dystonic patients.
Inter-Rater Agreement for the Ancillary Nonmotor Rating
Scales Included in the Unified Dystonia Rating Scale and
the Burke-Fahn-Marsden Rating Scale for Dystonia.
C.L. Comella, J. Wuu, S. Leurgans, The Dystonia Study Group
Department of Neurological Sciences, Rush Medical Center,
Chicago, Illinois, USA
Background: This study was designed by the Dystonia Study
Group (DSG) to assess dystonia rating scales used to evaluate
dystonia. The Unified Dystonia Rating Scale (UDRS) was de-
veloped by the Dystonia Study Group and rates dystonia in 14
body areas using a motor severity and a Duration of Dystonia
(DOD) factor; the Burke-Fahn-Marsden (BFM) rates dystonia
in nine body areas using a motor severity and PF factor. Ob-
jective: To assess the inter-rater agreement and internal con-
sistency of the ancillary, non-motor scales of the UDRS and the
BFM rating scale. Both rating scales have been shown to have
high inter-rater reliability but are felt to be cumbersome for
routine use. Each scale consists of a scale measuring motor
severity and an ancillary non-motor scale. The ancillary scale in
the UDRS is the DOD scale. The ancillary scale in the BFM is
a provoking factor (PF) scale. These ancillary scales add com-
plexity to the rating scale that complicates routine use in a
clinical setting. As a part of a larger study, this study assesses
the usefulness of the ancillary scales by determining the inter-
nal consistency and inter-rater reliability of the ancillary scales.
Methods: One hundred patients with dystonia of varying types
(focal, segmental, generalized) were videotaped using a stan-
dardized videotape protocol (58 women, 42 men; mean age, 51
years; range, 877 years; mean duration of dystonia, 14 years).
Ten patient videotape segments were edited onto each of 10
evaluation tapes. Twenty-five examiners each evaluated 2
evaluation tapes (20 patients) using the UDRS and BFM, in
random order. The raters were dystonia specialists not familiar
with the clinical history of the patients. After completing each
scale, the rater completed a questionnaire as to the ease of use
and clinical relevance of each scale. Pooled Kappa statistics
were used to assess the inter-rater agreement. Internal consis-
tency of each scale was assessed using Cronbachs . The level
of statistical significance was set at <0.01. Results: The total
scores of the UDRS and BFM showed good agreement among
raters with Intraclass Correlation Coefficients ranging from
0.71 to 0.78. The motor severity section of the UDRS and the
BFM had generalized weighted kappas from 0.52 to 0.91. The
ancillary scales showed a lower level of agreement, with scores
for the DOD of the UDRS ranging from .43 to .80 and for the
PF of the PFM from 0.37 to 0.89. The Cronbachs for the
motor severity scores for the original items was equivalent for
the severity and the ancillary rating scales, ranging from 0.75 to
0.89. Conclusions: This is the first study to evaluate the ancil-
lary rating scales for dystonia in a large group of patients
among multiple investigators and institutions. This study indi-
cates that the motor severity ratings show good to excellent
inter-rater agreement. Overall, both ancillary scales (the DOD
and PF) demonstrate less agreement among investigators and
increase the complexity of the assessments. The ancillary scales
Movement Disorders, Vol. 17, No. 5, 2002
for the UDRS and the BFM may not provide additional infor-
mation beyond that determined by motor severity scales. Modi-
fications of these scales may enhance their usefulness.
Analysis of the Duration of Efficacy of Botulinum Toxin
Type B in Patients with Cervical Dystonia
M.F. Lew
University of Southern California, Los Angeles, California, USA
Background: Intramuscular injections of botulinum toxin are
widely accepted as treatment of choice for cervical dystonia
(CD). The toxin acts by blocking the release of acetylcholine at
the neuromuscular junction, causing a dose-dependent reduc-
tion in muscle activity while producing a reversible paralysis at
the site of injection. Because the effects are temporary, repeat
injection is required periodically to prevent recurrence of
symptoms. Botulinum toxin type B (BoNT-B; Myobloc) has
been shown in clinical trials to significantly reduce pain and
postural abnormalities while improving physical functioning
and overall quality of life. Objective: To determine the duration
of efficacy of BoNT-B (Myobloc) injected into patients with
CD. Methods: Data on the duration of efficacy of BoNT-B
were compiled and analyzed from two placebo-controlled trials
and two open-label trials. In the placebo-controlled trials, 186
patients received a single injection of BoNT-B at a dose of
5000 U or 10,000 U divided among the affected neck muscles.
Efficacy was assessed by the Toronto Western Spasmodic Tor-
ticollis Rating Scale (TWSTRS)-Total Scores at Weeks 4, 8,
12, and 16. The first open-label trial included 145 patients and
evaluated escalating doses of 10,000 U, 12,500 U, and 15,000
U. Each patient was initiated on 10,000 U and received the
subsequent higher dose after returning to their baseline CD
status. TWSTRS-Total Scores were assessed every 4 weeks.
The second open-label extension trial included 427 patients.
The study was opened to patients who had participated in eight
previous BoNT-B clinical trials, as well as a small number of
drug-nave patients. Doses ranged from 2500 U to 25,000 U.
The change in TWSTRS-Total Scores from baseline to Week 4
was used to assess the effectiveness of repeated doses of
BoNT-B. Results: In the two placebo-controlled trials, the
mean time to return to baseline CD status was 12 to 16 weeks
in patients treated with BoNT-B. Compared with patients re-
ceiving placebo, patients treated with BoNT-B had a signifi-
cantly longer duration of treatment effect (P < 0.01 in both
studies). In the first open-label trial, the majority of patients
(<70%) in each dosing phase returned to baseline CD status
between 12 and 16 weeks. There was a trend toward higher doses
maintaining a longer duration of effect than the lower dose. With
the highest dose of 15,000 U, 1 patient continued to benefit from
treatment for 48 weeks. In the second open-label extension trial,
the mean time between treatments varied between 14 and 16
weeks for treatment sessions 1 through 9. Beginning with the tenth
treatment, there was a noticeable decrease in the mean time period
between treatments. The shorter mean time between treatments is
likely due to the fact that enrollment for many patients was trun-
cated when the sponsor ended the extension trial when BoNT-B
was approved by the U.S. FDA and in Europe for the treatment of
CD. Conclusion: Based on the results of two placebo-controlled
clinical trials and two open-label trials, the duration of efficacy of
BoNT-B in patients with CD is 12 to 16 weeks.