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Movement Disorders

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

2002 Movement Disorder Society


Fourth International Dystonia Symposium

Report on the Fourth International Dystonia Symposium

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


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


I. PATHOPHYSIOLOGY 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
Dystonia: Abnormal Movements Result from Loss of Inhi- gating before movements. This indicates a specific abnormality
bition in utilizing sensory input in preparation for a movement. We
M. Hallett subsequently found the lack of normal gating of P40 of tibial
Human Motor Control Section, NINDS, National Institutes of SEPs in patients with leg dystonia. In normal subjects, these
Health, Bethesda, Maryland, USA SEP components are gated because the input channels open for
the limb prior to the movement. Dystonia patients lack this
Dystonia is characterized by excessive movement, and this is process specifically for the affected limb, thus interfering with
likely due to a loss of inhibition. This review argues that the the sensory feedback control for the execution of the motor
defective inhibition in dystonia is surround inhibition, which program. Recent animal and human studies suggest that basal
is the suppression of unwanted movements. Evidence in favor ganglia play an important role in gating sensory inputs for
of decreased inhibition in dystonia includes deficient reciprocal guiding movements. One of the main hypotheses for the func-
inhibition, less inhibition in the blink recovery curve, reduced tion of the basal ganglia is to control or select automatic move-
short intracortical inhibition, reduced long intracortical inhibi- ments after learning. In fact, a recent human study showed
tion, and loss of GABA in the motor cortex with magnetic activation of the pallidum after learning a motor task, and it was
resonance spectroscopy. Loss of cortical inhibition in motor argued that the basal ganglia act as a flexible system for learn-
cortex can give rise to dystonic-like movements in primates as ing the association of sensory cues and movements. If this
has been shown with local application of bicuculline. Surround flexibility in associating sensory input and motor output is lost
inhibition is a function of the normal motor system. Leocani et by, for instance, repetitious execution of a learned motor act
al. evaluated corticospinal excitability of both hemispheres dur- such as writing, a fixed input-output mismatch may be the
ing a choice auditory reaction time task for extension of either consequence. Thus dystonia is regarded as a disorder of motor
left or right thumb. Transcranial magnetic stimulation (TMS) subroutine in which sensory input and motor output are defined
induced motor evoked potentials (MEPs) simultaneously in the for controlling frequently used movement.
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- Focal Hand Dystonia May Result from Aberrant Neuro-
tion. This has been extended by Sohn et al. who showed inhi- plasticity
bition of the MEP in the abductor digiti minimi muscle with N.N. Byl
movement of the flexor digitorum sublimis in the same hand. University of California, San Francisco, California, USA
Liepert et al. showed an increase in intracortical inhibition in a
hand muscle after practicing a task where that muscle was to be Focal hand dystonia is a very disabling disorder of move-
kept relaxed. The basal ganglia are likely to be the site of ment where co-contractions of the agonist and antagonist lead
genesis of dystonia and they are appropriately organized to aid to involuntary writhing,or twisting movements that interfere
in surround inhibition. Bu tefisch et al. have shown that task- with the performance of a task. This disorder is especially
dependent modulation of inhibition within the motor cortex is disabling for people in occupations that are heavily dependent
impaired in dystonia using an experimental design similar to on repetitive fine motor use of the hands. There has been in-
that of Liepert et al. Sohn et al. have shown defective inhibition creasing attention to the rise in repetitive strain injuries among
in dystonia of the surround muscle with a finger movement. computer users and musicians. Some of these individuals later
Learning how to influence surround inhibition may be helpful develop focal hand dystonia. In the last 20 years, it has become
in symptomatic treatment. 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
Sensory Deficits in Dystonia and Their Significance
that excessive, attended, stereotypical, near simultaneous hand
R. Kaji and N. Murase
movements could degrade the somatosensory representation of
Department of Neurology, Tokushima University Hospital,
the hand, disrupt the sensorimotor feedback loop and lead to
Tokushima, Japan
uncontrollable abnormal movements most specifically while
Sensory trick is a characteristic feature of dystonia. Dystonic performing a target task. We created a nonhuman primate
contractions in writers cramp were reproduced by stimulating model to generate support for this hypothesis and have since
group Ia afferents by high-frequency vibration (tonic vibration been trying to implement our findings in the clinic. With time,
reflex or TVR) and were abolished by blocking them with while focal hand dystonia is still considered idiopathic, there is
diluted lidocaine (muscle afferent block). These findings sug- increasing evidence that in some individuals, the condition rep-
gest an abnormal link between sensory input and motor output resent a case of aberrant learning. In this model, there is no
in dystonia. Recently marked disorganization sensory represen- lesion, but rather negative neural adaptation. The patient is in
tation of the digits in primary somatosensory cortex was found the best position to re-educate the nervous system and restore
in an animal model and patients with hand dystonia. Indeed, normal motor control. The purpose of this presentation is to
abnormal hand representation in the somatosensory cortex dis- review the principles of neuroplasticity, relate these principles
turbs normal motor-sensory integration in writing; if extrane- to the characteristics of focal hand dystonia, review the evi-
ous sensory input is fed back for subsequent movement, this dence that adult onset focal hand dystonia may represent a state
would set up a vicious cycle, causing further delapidation of of aberrant learning and integrate the principles of neuroplas-
motor control. To explore this sensorimotor link, Murase et al. ticity into a foundation of effective treatment.

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


Basal Ganglia Neuronal Discharge in Primary and Second- Transcranial magnetic stimulation (TMS) has proved a use-
ary Dystonia ful tool to study the pathophysiology of a number of disorders
M.K. Sanghera, W. Ondo, J. Jankovic, R.G. Grossman including dystonia. Shortening of cortical silent period (CSP)
Baylor College of Medicine, Houston, Texas, USA evoked by TMS has been reported in both cranial dystonia and
cervical dystonia. In these studies, evaluation of CSP has fo-
Pallidotomy (PAL) ameliorates levodopa-induced dyskine- cussed mainly on the affected muscles. Since it has been dem-
sias of Parkinsons disease (PD) and primary (1) dystonia onstrated that abnormality in central mechanisms is probably
(DYS) caused by a mutation of the DYT1 (TOR1A) gene. PAL more generalized than is apparent in focal dystonia, we studied
is less effective in improving secondary (2) DYS associated CSP in cranial, cervical and hand muscles in patients with focal
with lesions of the basal ganglia. We have examined putamen dystonia. High-intensity magnetic stimulation was delivered
(Put), globus pallidus externa (GPe) and the globus pallidus with a round coil centered at the vertex during maximal con-
interna (GPi) neurons in patients with 1 or 2 DYS (n 15), traction of muscles in 30 patients with focal dystonia (14 es-
and PD (n 78) to determine if there were differences in the sential blepharospasm and 16 cervical dystonia) and 20 normal
neuronal discharge rate and pattern between 1) awake and anes- controls. Our preliminary results showed that CSP is signifi-
thetized DYS and PD patients; 2) 1 and 2 DYS; 3) DYS cantly shorter in affected muscles in both patient groups. More-
patients who benefited and those who did not benefit from over there was also shortening of CSP in cranial muscles of
PAL; and 4) DYS and PD patients. Pallidotomy was performed patients with cervical dystonia. This finding supports previous
on 4 awake DYS and 72 awake PD patients, and on 11 anes- electrophysiological studies showing hyperexcitable blink re-
thetized DYS and 6 anesthetized PD patients. The ages of DYS flexes in patients with cervical dystonia. CSP was normal in
patients ranged from 951 years and those of PD patients hand muscles in both groups. These results indicate an impair-
ranged from 3978 years. Outcome for PAL was scored on a ment of the mechanisms of cortical inhibitory control in focal
global outcome score (GOS): 10 most beneficial; 0 no dystonia, which is more widespread in cervical dystonia.
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 Lasting Suppression of the Premotor Cortical Overactivity
in Arm Dystonia by Repetitive Transcranial Magnetic
irregularity of the discharge pattern in DYS and PD patients; 2)
Stimulation: A Clinical and PET Activation Study. Prelimi-
the mean discharge rate of Put neurons was low in both awake
nary Data
and anesthetized DYS and PD patients; 3) the mean discharge
S.R. Filipovic, H.R. Siebner, J.B. Rowe, C. Cordivari, W. Ger-
rate of both GPe and GPi was lower in DYS patients than in PD
schlager, J.C. Rothwell, R.S.J. Frackowiak, K.P. Bhatia.
patients in both awake and anesthetized conditions; 4) in DYS Institute of Neurology, Queen Square, London, United King-
patients, the mean discharge rate of GPe and GPi neurons were dom
similar, whereas the PD patients, the mean discharge rate of
GPe neurons was lower than the discharge rate of GPi neurons; Background: In previous functional imaging studies, patients
5) there was no correlation between the discharge rate or dis- with arm dystonia demonstrated increased movement-related
charge pattern of neurons in patients whose DYS was amelio- activity in the rostral premotor and prefrontal cortical areas
rated by PAL and those who did not benefit from the proce- compared with healthy subjects. Separately, it has been shown
that low-frequency repetitive transcranial magnetic stimulation
dure; 6) there was no significant quantitative differences in the
(rTMS) is capable of inducing a lasting inhibition of the tar-
rate or pattern of discharge of neurons in patients with DYS of
geted cortical area. Objective: We studied the clinical and re-
different etiology; and 7) PAL was most effective in patients
gional cerebral blood flow (rCBF) effects of rTMS applied over
with 1 genetic DYS (mean GOS SD 8.1 3.8) and
the premotor cortex in patients with arm dystonia. Methods:
idiopathic DYS (mean GOS SD 3.5 1.0). Unlike pallidal This is a single-blinded placebo-controlled crossover study.
neurons in PD patients which have been classified either as Intervention (real rTMS) was 30 minutes of the sub-threshold
pausers or bursters pallidal neurons in DYS patients dis- slow-frequency rTMS (intensity: 90% of the resting motor
played four distinct discharge patterns: GPe-irregular (52%), threshold; rate: 1Hz) over the left premotor cortex. Placebo
regular (24%), bursting (19%) and clustering (5%); and for (sham rTMS) was done using the same parameters but with
GPi-irregular (61%), regular (14%), bursting (6%) and cluster- the sham coil (i.e. no magnetic field induction but with the
ing (20%). The GPi discharge rate in awake DYS was one third same sound). The order of real and sham TMS was coun-
of that in awake PD. Dopamine agonists depress the firing of terbalanced across subjects, and sessions were separated by at
GPi neurons and it is possible that during dopa-dyskinesia, GPi least 7 days. Normalised rCBF was measured using H2O15 PET
discharge is depressed to the level seen in DYS. It is unclear immediately after the end of the each rTMS session. Each
why ablating the GPi should relieve DYS. The disruption of scanning session included three scans during paced freely se-
abnormal firing patterns, rather than changes in frequency, may lected finger movements of the right hand (active) alternating
produce the beneficial effects of PAL. 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
Distribution of Impairment of Cortical Inhibitory Mecha- (active vs. rest) and rTMS (real vs. sham). Two age- and sex-
nisms in Focal Dystonia: A Study of Silent Period Evoked matched groups of subjects were formed, idiopathic arm dys-
by Transcranial Magnetic Stimulation tonia group, and control group of healthy volunteers. We pre-
R. Cakmur, B. Donmez, F. Uzunel, H. Aydin, S. Kesken sent the results on the first 6 patients and 5 controls. Results:
Department of Neurology, Dokuz Eylul University Medical The contrast of movement selection (active) versus rest re-
School, SSK Tepecik Hospital, Izmir, Turkey vealed significant activation throughout the motor system, in-

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


cluding motor and premotor areas, cerebellum and basal gan- at the time of testing to date. The patients also reported that
glia. Moreover, real but not sham rTMS significantly reduced speech was less effortful after the block. Continuous abnor-
rCBF in the left premotor region (14, 2, +62), in both active malities in voice quality, such as harshness or breathiness, how-
and rest conditions. However, the significant (P < 0.05, cor- ever, were less affected. Acoustic analyses are being conducted
rected) Group rTMS interaction was found: the effect of from sentences coded to prevent knowledge of condition (pre-
rTMS in the premotor cortex (22, 0, +54) was significantly or post-block). Measures include the frequency and duration of
greater in the dystonic patients than controls. In addition, in both adductor and abductor voice breaks and sentence duration
both groups, there were several remote effects of rTMS includ- in sentences before and after block. Conclusions: Quantitative
ing reduced rCBF in the left medial parietal cortex (10, 60, data will be presented on the results of the afferent block on
+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 modic dysphonia. The data suggest an essential role of sensory
is possible, by the means of the slow rTMS, to reduce the feedback in the generation of laryngeal muscle spasms in the
metabolic overactivity of the premotor cortex in dystonic pa- disorder. It is unclear whether continuous voice quality abnor-
tients. These data also prove that rTMS is able to induce sus- malities represent an independent abnormality or a compensa-
tainable plastic changes in central nervous system functional tory strategy used by patients to cope with their disorder. The
networks. Although the time-course of recovery from the rTMS study supports the importance of sensory feedback in symptom
remains uncertain, this virtue of rTMS open an interesting per- generation for adductor and abductor spasmodic dysphonia.
spective for possible therapeutic application of rTMS in dys-
tonia and other movement disorders.
Secondary Cervical Dystonia Associated with Structural
Lesions of the Central Nervous System
The Role of Afferent Feedback in Symptom Generation in M.S. LeDoux and K.A. Brady
Spasmodic Dysphonia Department of Neurology, University of Tennessee Health Sci-
C.L. Ludlow, E.A. Mann, M. Allamarvdasht, E. Andersson, C. ence Center, Memphis, Tennessee, USA
Poletto Background: Cervical dystonia is the most common focal
Laryngeal and Speech Section, National Institute of Neurologi- dystonia, the majority of cases are idiopathic, and only a small
cal Disorders and Stroke, National Institutes of Health, percentage of patients have a family history of dystonia or other
Bethesda, Maryland, USA movement disorders. Pathophysiological mechanisms opera-
Background: In spasmodic dysphonia, involuntary spas- tive in solely or predominantly appendicular dystonias such as
modic bursts in the laryngeal muscles disrupt vocal fold vibra- writers cramp and Oppenheims dystonia, respectively, may
tion producing voice breaks, the primary symptom of the dis- not be directly applicable to axial dystonias. The localization of
order. Previously, we have found that electrical stimulation of structural lesions of the central nervous system associated with
laryngeal afferents will produce adductor (thyroarytenoid) secondary cervical dystonia may provide some insight into the
muscle responses in awake humans. Adductor muscle re- neural structures potentially involved in primary cervical dys-
sponses include an early ipsilateral thyroarytenoid muscle re- tonia. Objective: To test the hypothesis that structural lesions of
sponse, R1, and a late R2 muscle response. When pairs of the central nervous system associated with cervical dystonia
electrical stimuli were presented to afferents in the superior more commonly involve the cerebellum and its primary affer-
laryngeal nerve, R2 responses to the second stimulus of a pair, ent pathways than basal ganglia structures. Methods: The Na-
the conditioned stimulus, are reduced in frequency in awake tional Library of Medicine Gateway (from 1960) and a clinical
humans. Previous studies in both adductor spasmodic dyspho- database maintained by the senior author (from 1999) were
nia and abductor spasmodic dysphonia have demonstrated that searched for cases of secondary cervical dystonia associated
the suppression of conditioned responses was significantly re- with structural lesions of the central nervous system. Search
duced in both patient groups. This led to the hypothesis that terms included one or more of the following: dystonia, torti-
afferent feedback to the brain stem might have a role in the collis, cervical, secondary, and symptomatic. Lesion localiza-
generation of spasmodic bursts in the laryngeal muscles in tion and type, patient age, patient gender, head position, occur-
adductor and abductor spasmodic dysphonia. Objective: To de- rence of sensory tricks, and associated neurological findings
termine whether a temporary chemical block of the laryngeal were tabulated for each case. Results: The senior authors da-
sensory nerves on both sides of the larynx alters the frequency tabase contained four cases of secondary cervical dystonia as-
and duration of voice breaks in spasmodic dysphonia. Methods: sociated with structural lesions of the central nervous system:
Speech was recorded on two sets of 10 sentences prior to the pontine ischemic infarct, posterior thalamic ischemic infarct,
procedure. Laryngeal sensory thresholds in mm of Hg were cerebellopontine angle arachnoid cyst, and pontine hemor-
measured using 100 msec air puff stimuli to the epiglottis and rhagic stroke. A total of 21 additional cases were identified in
the mucosa covering the arytenoid cartilages. Two to 3 ml of the published literature since 1960. Structural lesions associ-
2% lidocaine was injected in the region of the superior laryn- ated with cervical dystonia were most commonly localized to
geal nerve above the thyrohyoid membrane on each side. Sub- the brainstem and cerebellum. The remaining cases were
jects were questioned regarding the onset of the sensation of equally divided between the cervical spinal cord and basal gan-
globus in the laryngeal area. Once this occurred, usually within glia. Although inconsistent, head rotation tended to be contra-
10 minutes post injection, the same 20 sentences were pre- lateral to lesion localization. Additional neurological abnor-
sented for repetition. Air puff sensory threshold testing was malities were present in the majority of patients with secondary
then repeated to confirm a block of the laryngeal afferents. cervical dystonia. Some patients with secondary cervical dys-
Results: Clinically significant reductions in voice breaks fol- tonia exhibited sensory tricks. Many patients with secondary
lowing the bilateral sensory block were noted in all participants cervical dystonia responded to treatments such as botulinum

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


toxin injections and anticholinergics that are used for patients in twisted postures. Despite the severity of these muscle fluc-
with primary cervical dystonia. Conclusions: The relative pau- tuations, Oppenheim noted that there was no muscle atrophy,
city of basal ganglia pathology and concentration of lesions in muscle weakness or any alteration in electrical excitability in
the brainstem, cerebellum, and cervical spinal cord in patients any of these patients that would account for their unusual motor
with secondary cervical dystonia suggests that dysfunction of symptoms. Further, the patients appeared cognitively intact
cerebellar afferent pathways may be important to the patho- suggesting that their symptoms were not due to hysteria as
physiology of primary cervical dystonia. 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
Cognitive Executive Function in Idiopathic Dystonia usually before the age of 28 years and manifests initially in
M. Jahanshahi,1 J. Rowe,2 R. Fuller1 distal limbs and later progresses to affect multiple body parts.
Department of Clinical Neurology, Institute of Neurology, The This disorder is most prevalent amongst Ashkenazi Jews and is
National Hospital for Neurology and Neurosurgery, London; now known to be caused by deletions within the protein coding
Department of Clinical Psychology, East London and The City region of the TOR1A (DYT1) gene. The heterozygous GAG
Mental Health Trust, Homerton Hospital, London, United deletion in TOR1A has low penetrance, approximately only
Kingdom 30% of people with the mutation develop clinical symptoms,
which initially led to the hypothesis of an autosomal recessive
Dystonia is a movement disorder considered to be due to mode of inheritance. The TOR1A gene encodes a novel protein
basal ganglia dysfunction and imaging studies have revealed termed torsinA whose function is currently unknown, although
functional abnormalities in fronto-striatal areas in the disorder. sequence homology studies have revealed a similarity with the
Objective: To investigate the functional significance of the AAA+ family of ATPases which perform chaperone-like func-
frontal hyperactivity demonstrated in dystonia in imaging stud- tions and assist in protein trafficking and membrane fusion.
ies by examining executive function and working memory in Despite the identification of deletions within the TOR1A gene
which the prefrontal cortex is known to be involved. Methods: in Oppenheims dystonia, the etiology of this disease still re-
We assessed 12 patients with idiopathic Dystonia and 12 age- mains elusive and effective therapies are limited. During the
matched normal controls. All subjects completed tests of first last two decades several biochemical studies have been carried
letter, category and alternating category word fluency, the Wis- out in patients with childhood-onset dystonia muscularum de-
consin Card Sorting test, the Stroop Colour Word Intereference formans, although no consistent biochemical abnormality has
test, the missing digit test, a test requiring generation of self- been identified. Further, no gross neuropathological abnormal-
ordered random number sequences, the paced serial addition ity is observed postmortem in primary childhood-onset gener-
test, a test of Conditional Associative Learning, and finger alized dystonia, in contrast to other degenerative disorders in-
tapping and peg insertion under unimanual, bimanual and dual cluding Wilsons disease and Parkinsons Disease, where dys-
task conditions. Results: Although the patients had lower scores tonia is a prominent symptom, further complicating the search
than the controls on all tests, after co-varying out group differ- for the etiology of this debilitating disorder. Several other
ences in depression and premorbid IQ, the patients did not forms of dystonia are now known to be caused by a deficit in
significantly differ from the controls on any of the measures of striatal dopamine (DA). For example, point mutations within
executive function used other than extent of decline in tapping the tyrosine hydroxylase (TH) gene, the rate-limiting enzyme in
with the right hand under dual task conditions when simulta- the DA synthesis pathway, within the GTP cyclohydrolase
neously inserting pegs with the left hand. Conclusion: These gene, and within the DA D2 receptor gene result in a dystonic
results suggest that unlike other movement disorders associated phenotype in man. Administration of pharmacological agents
with fronto-striatal dysfunction such as Parkinsons disease and that block DA D2 receptors in vivo can similarly result in a
Huntingtons disease, Dystonia is not associated with deficits dystonic phenotype as can mechanical or ischemic lesions of
on tests of executive function and can be considered to be the striatum. Further, torsinA mRNA and protein are highly
primarily a motor disorder. 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
II. OPPENHEIMS DYSTONIA examine comprehensively markers of DA signaling within the
striatum of three genotypically confirmed DYT1 dystonia
brains. Methods: Biochemical indices of striatal DA transmis-
Biochemistry of Oppenheims Dystonia sion were examined by measuring the tissue content of DA and
S.J. Augood its metabolites DOPAC and homovanillic acid (HVA), whereas
Neurology Research, Massachusetts General Hospital and markers of DA transmission were examined by quantitative
Harvard Medical School, Charlestown, Massachusetts, USA autoradiography using tritiated ligands for the DA (mazindol)
and vesicular (dihydrotetrabenazine DHTB) transporters (pre-
Background: In 1911 Herman Oppenheim coined the term synaptic) and DA D1 (SCH-23390) and DA D2 (YM-09151-2)
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 confirmed DYT1 dystonia cases. Results: We found a 23%
hypertonia in these children resulted in their muscles fluctuat- reduction in striatal DA content and a 48% increase in dopa-C
ing between involuntary contraction and tonic spasms, resulting content in DYT1 dystonia. Although neither of the changes

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


alone was statistically significant, these absolute values trans- the degradation of integral membrane protein substrates. Yet
lated into a significant increase (+71%) in striatal dopa-C/DA another AAA+ protein, p97/cdc48p, forms a heteromeric com-
ratio in DYT1 dystonia. These biochemical indices of DA plex that dislocates ubiquitinated substrates from the ER mem-
transmission are indicative of an intact dopaminergic nigro- brane. Based on the data described below and by analogy to the
striatal system, although the increased dopa-C/DA and HVA/ functions of some of the AAA proteins described above, we
DA ratios are consistent with an increase in DA turnover in the present a working hypothesis for Torsin A function. Overex-
DYT1 striatum compared to controls. Biochemical evaluation pression of the dystonia associated E Torsin A in cultured
of 2 other cases of DYT1 dystonia exist in the literature, and in cells induces formation of concentric whorls of endoplasmic
both cases striatal DA and HVA tissue content was found to be reticulum membrane called karmellae.We established stable
similar to controls, however, tissue DOPAC content was not cell lines where expression of human Torsin A (WT, E, or the
reported. Examination of markers of post-synaptic DA trans- presumably ATPase deficient E171Q) is under the control of an
mission revealed a similar picture to the biochemical data. Do- inducible promoter. When the Torsin A is recovered from cell
pamine D1-like and D2-like binding were decreased in the lysates by metal ion affinity chromatography, -[32P] -ATP can
DYT1 striata, although in neither case did the mean reduction be UV crosslinked to both the WT and E Torsins. As in
achieve significance. In particular, a 29% reduction in D1-like mammalian cells, expression of E but not WT Torsin A in-
and a 40% reduction in D2-like binding were measured. Thus, duced karmellae formation. Furthermore, expression of the pu-
the biochemical data coupled with the receptor autoradiography tatively ATPase deficient Torsin A also induced karmellae for-
are highly suggestive of an imbalance in DA signaling within mation. These results indicate that a novel mutation predicted
the DYT1 striatum, in particular an increase in DA turnover. to affect Torsin As enzymatic activity gives a cellular pheno-
Conclusions: These data are consistent with the hypothesis that type similar to that observed by the disease-causing mutation.
in DYT1 (Oppenheims) dystonia mutant torsinA may impact, Karmellae formation is often induced upon overexpression of
preferentially, on the dopamine system in vivo to perturb stria- integral membrane proteins such as HMG-CoA reductase or
tal signaling. Thus, our findings will be presented and dis- cytochrome P-450. We also found that Torsin is present in
cussed in light of the recent anatomical data localizing torsinA purified canine pancreatic rough microsomes. In both these
immunostaining to symmetrical, putative dopaminergic, syn- membranes and in the S2 cells Torsin is not an integral mem-
apses in the primate striatum. 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-
Cell Biological and Biochemical Analysis of Torsin A edge, Torsin is the first non-integral protein to be associated
B. Lauring with karmellae formation. Sub-fractionation of the purified ER
Department of Pathology, Taub Institute for Research on Alz- membranes showed that while a fraction of Torsin is soluble in
heimers, Disease and the Aging Brain, College of Physicians the ER lumen, another fraction is associated with the translo-
& Surgeons, Columbia University, New York, New York, USA con. We also show that these Torsin-containing translocon
Torsin dystonia is an autosomal dominant primary dystonia complexes isolated from mammalian ER membranes are ca-
caused by a one amino acid deletion in the gene encoding pable of unfolding cholera toxin, a protein that normally un-
Torsin A, a member of the AAA+ family of ATPases. Torsin A folds in the ER, in an ATP-dependent manner. Given that dom-
is a lumenal resident endoplasmic reticulum (ER) protein of inant mutations in Torsin A cause a phenotype usually pro-
unknown function. Soluble and integral membrane proteins en- duced by accumulation of integral membrane proteins, the
tering the secretory pathway enter the ER through the translo- translocon association of Torsin , and the potential ability to
con, which is a multiprotein machine that co-translationally unfold substrates, we hypothesize that Torsin A is involved in
translocates proteins across the ER membrane. In the ER pro- removal of proteins, particularly integral membrane proteins,
teins must fold and oligomerize with their binding partners. from the ER. We further speculate that Torsin A is an unfoldase
There also exists an elaborate quality control mechanism in the that directs ERAD substrates into the translocon as part of the
ER which identifies misfolded or improperly oligomerized pro- ERAD (ER-associated degradation) response.
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 Distribution of Torsin A in the Developmental and Adult
a dizzying array of cellular processes are found in many sub- Rat Brain
cellular locations and are structurally divergent. They do how- S.R. Oberlin,1 M. Konakova,2 S.M. Pulst,2,3 M-F. Chesselet4
ever all share the so-called AAA+ ATPase domain. A common Department of Neurology, University of California-Los Ange-
molecular mechanistic theme among the best studied members les, Los Angeles, California; 2Rose Moss Laboratory for Par-
of the family is the that the energy from ATP hydrolysis drives kinson and Neurodegenerative Diseases, CSMC Burns and
conformational changes not only in the AAA+ ATPases, but Allen Research Institute; 3Division of Neurology, Cedars Sinai
often in associated substrate proteins as well. In many cases, Medical Center, UCLA School of Medicine, Los Angeles, Cali-
these ATPases drive disassembly or unfolding reactions fornia; 4Department of Neurology and Brain Research Insti-
Loosely defined, many AAA proteins function in protein qual- tute, University of California-Los Angles, Los Angeles, Cali-
ity control reactions In E. coli, the hexameric Clp A protein fornia, USA
unfolds proteins pre-tagged for degradation and feeds them into Dystonia is a neurological movement disorder characterized
the lumen of the barrel shaped Clp P protease for degradation. by sustained muscle contractions causing abnormal posture and
Other AAA+ proteins residing in the E. coli plasma membrane repetitive, twisting motions. Early-onset dystonia is thought to
or in mitochondrial membranes effect both the dislocation of be a developmental disorder of the basal ganglia, however,
proteins from membranes and, via metalloprotease domains, there is currently no evidence of neurodegeneration. This most

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


common form of primary dystonia has been linked to a 3 base- served when E2 torsinA is transiently expressed in vitro are not
pair GAG deletion in the DYT1, which encodes the novel observed in the E2 knock in mice. A comparison of the phe-
protein Torsin A. In this study we identify the distribution of notypes of the knock out and knock in mice suggest that the
Torsin A in the developmental and adult rat brain using two DYT1 mutation does not obliterate torsinA function. Further,
specific antibodies generated against Torsin A, TR1 and TR2. the fact that the E2 knock in mice display an abnormal behav-
We find that there is an overall increase in the level of expres- ioral phenotype in the absence of morphological abnormalities
sion of Torsin A during development. Expression is specific to of ER suggests that these morphological changes are not re-
the cytoplasm of neuronal cell bodies and fibrous processes quired for mutant torsinA to produce motor dysfunction. Fur-
with some indication of staining within the nucleolus. At P1 ther analysis of these torsinA mutant mice will help to elucidate
expression is confined to specific regions including the brain- the function of torsinA and how the DYT1 mutation disrupts
stem, pontine nucleus, specific thalamic nuclei, and the stria- this function to lead to abnormal motor behavior.
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 A Transgenic Mouse Model for DYT1 Dystonia
Torsin A is ubiquitously expressed throughout most regions of P. Shashidharan, M.F. Brin, P. Gujjari, D. Sandu, and C.W.
the brain. The most significant change in the level of expression Olanow
was observed in the cholinergic interneurons within the stria- Department of Neurology, Mount Sinai School of Medicine,
tum. Beginning at P7 Torsin A expression in cholinergic inter- New York, New York, USA
neurons increases compared to the level of expression in me-
dium spiny neurons. This change in the level of intensity peaks Childhood-onset torsion dystonia is a progressive disabling
at P14, continues through P21, and declines to adult levels by disorder of motor control, characterized by abnormal, involun-
P28. This pattern of intensity may indicate that Torsin A is tary muscle contractions. A three base pair (GAG) deletion in
important in regulating the development of cholinergic inter- the coding region of DYT1 gene has been identified as a cause
neurons and may suggest a potential mechanism explaining the for this disorder. The DYT1 gene encodes for a protein called
effectiveness of anti-cholinergic drugs in the treatment of pa- torsinA, which is expressed in brain and many peripheral tis-
tients with early-onset dystonia. 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
Animal Models torsinA mutation on brain function, we have developed trans-
W. Dauer genic mice expressing human mutant torsinA. Genotype of
Columbia Presybterian, New York, New York, USA mice was determined by PCR amplification and restriction
analysis of genomic DNA from tail biopsies. The transgenic
Primary dystonia research has been hampered by the lack of mice were able to feed normally and their weight gains were
an etiological specific animal model of the disease. DYT1 (Op- comparable to that of wild type controls. The mice were able to
penheims) dystonia, the most common form of early-onset reach sexual maturity and produce normal sized litters. Some
primary dystonia, is an autosomal dominant disorder caused by but not all of the transgenic mice exhibited abnormal circling
an in-frame GAG deletion (glutamic acid) in the TOR1A gene. and hyperkinetic movements. Approximately 35% of trans-
The TOR1A gene encodes torsinA, a AAA protein of unknown genic mice developed these abnormal hyperkinetic and circling
function that resides in the ER. We have generated torsinA behaviors. The pattern of abnormal motor activity developed in
knock out mice and find that while these animals are born with mice between 3 and 10 weeks of life and remained for the rest
normal Mendelian frequency, they fail to feed and die within 24 of their lives. As not all-transgenic mice show this abnormal
hours of birth. TorsinA knock out pups appear grossly normal, phenotype, other secondary factors may be necessary for the
and histological analysis of the brain and other organs is unre- precipitation of the symptoms, which is presently not known.
markable. No abnormalities have been observed in a number of Interestingly the percentage of mice exhibiting the abnormal
defined neuronal populations, including dopaminergic neurons, symptoms is comparable to the human condition. In humans,
and cranial, olfactory and sensory neurons. Further, torsinA 30 to 40% of the mutant gene carriers develops abnormal motor
knock out primary cortical cultures appear grossly normal, and function. This transgenic mouse model will give us an oppor-
do not display a deficient ER stress response. We have also tunity to address some of these questions and may provide
used gene targeting to generate a pair of torsinA knock in mice clues to the pathophysiology of childhood onset dystonia.
that lack either the disease-associated glutamic acid deletion [Note: This work was supported by the National Institutes of
(E1) or a downstream glutamic acid (E2). Both of these muta- Health (NINDS NS43038) and by the Bachmann-Strauss Dys-
tions cause torsinA to acquire an abnormal punctate pattern of tonia and Parkinson Foundation, New York.]
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 Dominant TorsinA Mutations in Cellular Systems
wild type littermates. While these mice do not display any C.A. OFarrell,1 D. Hernandez,1 A.B. Singleton,1,2 M.R. Cookson1
obvious abnormal involuntary movements, they are signifi- 1
Mayo Clinic Jacksonville, Jacksonville, Florida; 2National In-
cantly impaired in rotarod performance. The dopaminergic sys- stitute on Aging, Bethesda, Maryland, USA
tem of these mice appears normal, as assessed by their motor
response to GBR-12909 (blocks dopamine transporter), quan- Dominant mutations in the gene encoding for the novel pro-
titative autoradiography for D1 and D2, and dopamine trans- tein torsinA are associated with a familial form of dystonia. To
porter immunostaining. The morphological abnormalities ob- date, two apparently dominant mutations have been described,

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


both in-frame deletions in the C-terminal portion of the protein. deposition is associated with diverse neurological disorders in-
The function of torsinA has not been identified. However, re- cluding neurodegenerative diseases caused by polyglutamine
sults from several laboratories suggest that at least one of the expansion such as spinocerebellar ataxias and Huntingtons
mutant forms may have a propensity to form intracellular in- disease. Immunocytochemical analyses of inclusions termed
clusions when transiently expressed at high levels in cultured Lewy bodies, a clinical characteristic of post-mortem brains
cells. It is not clear how the mutation exerts a dominant effect from patients with Parkinsons disease, revealed an intense
in the presence of wild type protein. There are three formal reactivity for torsinA. Among movement disorders, dystonia
possibilities for possible effects of the mutation on protein remains poorly understood due to an absence of neuronal de-
function. Firstly, mutant torsinA may exert a toxic gain of generation, thus rendering it difficult to pathologically define.
function. Secondly, the expression of mutant torsinA may de- Progress toward delineating torsin expression and localization
crease wild type function, thus acting as a dominant negative. has been reported but intracellular activities have not been elu-
Finally, it is possible that dystonia occurs because two fully cidated. We exploited the experimental advantages of C. el-
functional copies of the gene are required (haploinsufficiency). egans to investigate torsin function using an in vivo assay for
To distinguish between these possibilities will require several examining states of intracellular protein aggregation. A nema-
approaches. In the present study we have used cell culture tode torsin homologue, TOR-2, localized to cellular sites of
models to dissect the effect of expression of mutant torsinA on polyglutamine repeat-induced fluorescent protein aggregation
the localization of wild type protein. We have been able to and dramatically suppressed the formation of inclusions in
reproduce the previous reports of mislocalization of E303- transgenic animals. Suppressive effects of torsin overexpres-
torsinA in cytoplasmic inclusions in neuronal or non-neuronal sion persisted as animals aged, whereas a mutant torsin was
cell lines. Wild-type protein expressed at similar levels did not incapable of ameliorating aggregate formation. Antibody stain-
produce such aggregates. However, we have not seen such ing of transgenic animals using antisera specific to TOR-2 in-
inclusions formed with a more recently reported 18 base pair dicated this protein was highly localized to sites of protein
(F323-Y328) deletion, raising the possibility that the forma- aggregation, wherein it appeared to form a complex with the
tion of these intracellular inclusions is specific to E303. Simi- aggregated protein, as determined by co-immunoprecipitation.
lar experiments in virally transduced post-natal mouse brain The intracellular response to protein misfolding represents an
primary neuronal cultures will be presented. Preliminary im- undefined biological mechanism with significant consequences
munoprecipitation data suggests that wild type torsinA and ? ? for therapeutic intervention; implication of torsins in this pro-
303 torsin A interact. However, steady state levels of torsinA cess provides a context for better understanding dystonia and
protein do not appear to be affected by the level of mutant its relation to other disease mechanisms.
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. 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-
In Vivo Suppression of Protein Aggregation by a C. elegans smith,2 H. Boston,1 D. Slater,1 J. Wilbur,1 D. Schuback,1 C.
Torsin Homologue Kamm,1 L. Ozelius,3 V. Ramesh,1 P.I. Hanson2
G.A. Caldwell, E.G. Sexton, S. Cao, J.P. Bevel, K.A. Caldwell Molecular Neurogenetics Unit, Department of Neurology,
University of Alabama, Department of Biological Sciences, Massachusetts General Hospital, and Neuroscience Program,
Tuscaloosa, Alabama, USA Harvard Medical School, Boston, Massachusetts; 2Department
of Cell Biology and Physiology, Washington University School
Torsion dystonia is an autosomal dominant movement dis-
of Medicine, St. Louis, Missouri; 3Department of Molecular
order characterized by involuntary, repetitive muscle contrac-
Genetics, Albert Einstein College of Medicine, Bronx, New
tions and twisted postures. The most severe early-onset form of
York, USA
dystonia has been linked to mutation in the human TOR1A
(DYT-1) gene encoding a protein termed torsinA. While caus- Most cases of early onset torsion dystonia are caused by loss
ative genetic alterations have been identified, the function of of a glutamic acid in the carboxy terminal of torsinA. This
torsinA and molecular mechanism underlying dystonia remain autosomal dominant neurological disorder is characterized by
unknown. Phylogenetic analysis of the torsin protein family abnormal movements, believed to originate from neuronal dys-
indicates these proteins share distant sequence similarity with function in the basal ganglia of the human brain. TorsinA is a
the large and diverse family of AAA+/HSP/Clp-ATPase pro- member of the ATPases associated with a variety of cellular
teins. We have established the nematode, Caenorhabditis el- activities (AAA+) superfamily of proteins that mediate chap-
egans, as a model system for examining torsin activity. C. erone functions involved in conformational modeling of pro-
elegans has 959 somatic cells, including a nervous system con- teins, protection from stress, and targeting of proteins to cellu-
sisting of only 302 neurons (vs. >100 billion in the human lar organelles. In this study, the intracellular distribution and
brain). However, this simple nematode is capable of compli- levels of endogenous torsinA were evaluated in the neuroen-
cated behaviors, many of which are directly associated with docrine cell line, rat pheochromocytoma PC12, following dif-
specific neurotransmitters (dopamine, serotonin, acetylcholine) ferentiation and stress. TorsinA, apparent MW 37 kD, co-
and neuromuscular responsiveness. The ability to rapidly per- fractionates with markers for the microsomal/endoplasmic re-
turb protein function genetically, in the context of an intact and ticulum (ER) compartment and resides primarily within the ER
visually transparent animal with defined neuronal processes, is lumen. TorsinA-immunoreactivity co-localizes with the lumen-
highly advantageous for analyses linking genetic abnormality al ER protein, protein disulfide isomerase (PDI), and the ve-
to anatomical structure and cellular function. Aberrant protein sicular marker, VAMP (synaptobrevin), extending throughout

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


neurites to their endings, with accumulation at varicosities. Mutations in torsinA, a member of the AAA family of
Levels of torsinA did not increase notably in response to nerve ATPases, are associated with early onset-dystonia. A closely
growth factor-induced differentiation or heat shock. Among a related homologue, torsinB, has also been described, although
number of stress conditions tested, oxidative stress resulted in the significance of this second form is not clear. Here we de-
a marked increase in both the apparent amount and MW of scribe the cloning of a full-length cDNA for torsinB and dem-
torsinA. These studies are consistent with a role for torsinA in onstrate that in transfected cells it has similar properties to
ER-based chaperone functions, with a high sensitivity to oxi- torsinA. The limited previous studies of torsinB have suggested
dative stress. Mutant torsinA may interfere with and/or com- that the molecular weight is greater than that of torsinA. We
promise these ER functions, especially in dopaminergic neu- looked for alternate start sites in torsinB using 5 RACE and
rons, which have high levels of torsinA and are intrinsically identified two products, which were both sequenced. We were
vulnerable to oxidative stress. 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
Microarray Analysis of a Cell Culture Model of Early- and found, similar to previous reports, that there is a single
Onset Dystonia Linked to Torsin A Mutations major mRNA species of approximately 2.7 kb. By transfecting
M.J. Baptista,1 C. OFarrell,2 M.R. Cookson1 cells with a full length cDNA constructs we saw that, like torsin
Neurogenetics Laboratory, NIA/National Institutes of Health,
A, torsin B is subject to N-glycosylation but not O-glycosyla-
Bethesda, Maryland; 2Neurogenetics Laboratory, Mayo Clinic
tion. Polyclonal antibodies raised against regions of low ho-
Jacksonville, Jacksonville, Florida, USA
mology between torsinA and torsinB were used to confirm that
Early-onset torsion dystonia is a movement disorder charac- both proteins are localized to PDI-positive structures in trans-
terized by sustained muscle contractions and abnormal posture. fected cells, suggesting that both proteins reside in the endo-
A deletion in a conserved region of the torsinA gene, resulting plasmic reticulum. When expressed in cell lines, torsinB has
in the loss of a one of a pair of glutamate residues (E302/303), similar electrophoretic mobility to torsinA but is more basic,
has been detected in a large number of patients with chromo- consistent with predictions from the cDNA sequence. Using
some 9-linked primary dystonia (DYT1). However, mutations antibodies designed to a common region of both torsin proteins,
in torsinA are not fully penetrant and some genetic heteroge- we show that torsinA is much more abundant than torsinB in
neity has been noted, suggesting that additional genetic fac- human cerebellum brain extracts. These results show that
tor(s) may play a role in the development of this disease. The torsins A and B are similar proteins, although there are sub-
first aim of the current study was to use a cell culture model of stantial differences in the abundance of the two homologues.
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, An Epidemiological Survey of Dystonia (ESD) Within the
the second aim of the current study was to identify genes whose Entire Population of Northeast England over the Past 9
expression is altered by torsinA in the hope of identifying novel Years
markers of cellular dysfunction caused by the presence of these A.G. Butler,1 P.O.F. Duffey,2 M.R. Hawthorne,3 M.P. Barnes4
mutations. Clonal cell lines over-expressing either wild type 1
ADDER, Bath Cottage, Dinsdale Park, Middleton St. George,
torsinA or the E302/303 mutation were generated by stable Co. Durham; 2York District Hospital, Wigginton Road, York;
transfection of HEK293 cells with appropriate cDNAs in mam- 3
The North Riding Infirmary, Newport Road, Middlesbrough,
malian expression vectors. We measured torsinA expression
Cleveland; 4University of Newcastle, Hunters Moor Rehabili-
using both RT-PCR and protein and identified several clones of
tation, Centre, Hunters Road, Newcastle-upon-Tyne, United
both wt and E302/303 with similar levels of expression. Simi-
lar to previous studies, we noted the presence of ER-derived Kingdom
intracellular inclusions in E302/303 transfected cells, which The Epidemiological Survey of Dystonia (ESD) was started
were maintained after selection and serial passage of the cells.
in May 1993 with just 143 people known to have dystonia in
We then used the oligo-based U95A GeneChip (Affymetrix,
Santa Clara, CA) to globally compare the expression levels of the northeast of England and Cumbria. By the time of the 3rd
12,500 non-redundant cDNAs and ESTs. The microarray data International Dystonia Conference (Florida, June 1996), there
will be confirmed by quantitative RT-PCR using SYBR green were a total of 500+ cases who had been diagnosed, and by
as a reporter. It is expected that identification of additional gene June 2001 the total number of primary and secondary dystonics
families regulated by over-expression of torsinA, both wild was over 1,100 people within the geographical region. The
type and the E302/303 mutation will provide additional in- research has proven that dystonia is the third most prevalent
formation towards defining a pathway leading to dystonia. 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-
Characterization of Torsin B and Expression in Human search to date is that there has been a positive identification that
Brain Relative to the Dystonia-Associated Torsin A Protein 28.7% of all these cases have a proven member of the family
C.A. OFarrell,1 P.J. Lockhart,1 S. Lincoln,1 D. Hernandez,2 with a form of dystonia, i.e., with a definite and genetic con-
A.B. Singleton,2 M.R. Cookson2 nection within the dystonic family, thus increasing the present
Department of Neuroscience, Mayo Clinic Jacksonville, Jack- known incidence of familial dystonia. This is the first time that
sonville, Florida; 2Laboratory of Neurogenetics, National In- an epidemiological study has attempted to identify all cases of
stitute on Aging, Bethesda, Maryland, USA dystonia in a well-defined population. All other previous dys-

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


tonia epidemiologies have either taken medical referral centres fected cells. We have subsequently adapted this approach to a
as the basis for their statistics or have been flawed in that either format compatible with high throughput screening by seeding
ascertainment of their diagnosis was incomplete or the nature infected cells into 384-well microtiter plates, processing for
of their criteria was limited in some way. In this case, a definite torsinA immunofluorescence using automated liquid handling
geographical region has been taken and as far as is possible devices, and rapidly capturing digital images of each well with
everyone known to have dystonia who lives or is treated within an automated fluorescent microscope. Digital images are ana-
that region has been included. Over 12.1% of these people were lyzed using image analysis software (Metamorph; Universal
not registered at any hospital or medical centre. As previously Imaging, West Chester, PA) to determine both the density and
reported, Darlington, a small town in the North East of En- average size of mutant aggregates per well. This system thus
gland, with a known population of 101,766 individuals within serves as a sensitive, cell-based assay to evaluate factors that
45,383 households was the subject of an intensive epidemio- may resolve the mutant torsinA aggregates, and it is currently
logical study undertaken in 1996 (note change in date). This being used to screen a library of FDA-approved compounds
study has continued to date and currently this town has exactly provided by the National Institute of Neurological Disorders
53 people within it with a form of dystonia, thus indicating a and Stroke (NINDS).
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 A Drosophila Model of Early-Onset Torsion Dystonia
musicians, almost more than any other occupation, make very Y.H. Koh, K. Rehfeld, B. Ganetzky
fine repetitive movements of the fingers and hands and that University of Wisconsin Madison, Madison, Wisconsin, USA
very small dystonic tremors or postures, that are not noticeable,
nor cause a problem in others, can be devastating to them. Two mutations in the DYT1 gene, encoding the TorsinA
Dystonia is not a rare disorder, but it does remain little known protein, are linked to early-onset torsion dystonia, the most
or recognised, even within medical circles. Research, such as common and severe form of this disorder. However, the cellu-
the above, has proven it has a known prevalence of less than 1 lar and molecular mechanisms of pathogenesis underlying
in 2,000 people in the general population and even higher in early-onset torsion dystonia are still not clear and the cellular
specialist groups. 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
Development of a cell-based assay to screen compounds for the cellular and molecular mechanisms of pathogenesis under-
resolution of mutant torsinA aggregates lying early-onset torsion dystonia. To examine Drosophila Tor-
D.C. Bragg, J.D .Wilbur, X.O. Breakefield sin (Dtor) functions in vivo, we are using inhibitory RNA
Molecular Neurogenetics Unit, Massachusetts General Hospi- (RNAi) to reduce expression of the Dtor gene by creating trans-
tal, Charlestown, Massachusetts, USA genic lines that express Dtor double-stranded RNA. Immuno-
staining with anti-Dtor antibodies demonstrates that Dtor pro-
Most cases of early-onset, generalized torsion dystonia have
tein levels are reduced in neurons and muscles of these flies.
been attributed to the deletion of a glutamic acid residue in the
Furthermore, reduction of Dtor expression in these lines is
carboxy terminus of torsinA. Previous work in our laboratory
associated with a signficant alteration in the morphological
has demonstrated that overexpression of mutant, but not wild-
appearance of synapses at the larval neuromuscular junction.
type torsinA in cultured cells by DNA transfection results in its
accumulation in multilamellar inclusions that appear to derive Thus, normal levels of Dtor are required either directly or in-
from the endoplasmic reticulum. We recently developed an directly for normal synaptic development in Drosophila. In a
improved delivery strategy to express either mutant or wild- complementary approach, we have created transgenic strains of
type torsinA in cultured cells using herpes simplex virus type 1 Drosophila that express either normal human TorsinA (HtorA)
(HSV-1) amplicon-based viral vectors. The coding sequence of or one of two mutant forms of this protein. Normal and mutant
either wild-type or mutant torsinA was cloned into an HSV-1 forms of HTorA were expressed in selected populations of
amplicon plasmid and packaged as HSV amplicon vectors us- neurons and muscles to examine the subcellular localization of
ing a helper virus-free system. The resulting vectors contain the HtorA and the effect of expression on synaptic morphology.
torsinA sequences under the control of the cytomegalovirus Normal HtorA is distributed broadly over neuronal soma or
promoter with a separate expression cassette encoding the en- muscle surfaces. However, mutant Htor containing a single
hanced green fluorescent protein to allow identification of in- amino acid deletion exhibits strong clustering of around cellu-
fected cells. These vectors express either wild-type or mutant lar membranes in neurons and muscles. Furthermore, expres-
torsinA in human glioma cells at extremely high efficiencies sion of the same mutant protein in motor axons or muscles
(approximately 80-90% of cells in culture) and at expression induced morphological changes at glutamatergic synapses at
levels which, compared to those achieved by DNA transfection, the larval neuromuscular junction. Over-expression of a second
more closely resemble those of the endogenous protein. Fol- mutant form HtorA, containing a six-aminoacid deletion, in-
lowing infection with these amplicon vectors, cells expressing duced similar defects in synaptic morphology, even though the
mutant, but not wild-type, torsinA also form discrete aggre- cellular distribution of this mutant protein was more like that of
gates that can be visualized via immunofluorescence. Western normal. At present, we are investigating in more detail the
blot analysis confirmed that this expression system produces behavioral, morphological and electrophysiological phenotypes
equivalent levels of either mutant or wild-type protein in in- in flies expressing Dtor RNAi and the various forms of Htor.

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


III: OTHER GENETIC DYSTONIAS 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
Classification and Clinical Features novel locus, DYT13. The phenotype in this family is charac-
S.B. Bressman terized by prominent cervical-cranial and upper limb involve-
Beth Israel Medical Center, New York, New York, USA ment with early onset and mild severity. Linkage and haplotype
analysis placed the locus within a 22 cM interval on the short
Classification schemes for the many etiologies of dystonia arm of chromosome 1. At present, four unrelated families have
are under constant revision, reflecting increasing knowledge been reported with rapid onset dystoniaparkinsonism (RDP,
about the many genetic causes and widening clinical experi- DYT12). RDP is characterized by abnormal movements typical
ence with specific dystonia genes. Primary (torsion) dystonia of both dystonia and parkinsonism. These symptoms can come
(PTD) has been defined as a group of disorders characterized on rapidly (over hours to days) followed by stable symptoms
clinically by dystonic movements and postures as the only for years. Using two of the families, a gene for RDP was
overt sign except for tremor, and also having no acquired or mapped to chromosome 19q13 (DYT12) in an 8 cM region
exogenous cause or evidence of neural degeneration. The sec- between D19S587 and D19 S900. Both an Irish family with 8
ondary dystonias are comprised of all other dystonic condi- affected individuals and a family from Poland with 4 affected
tions; these include inherited or complex disorders that may or members have been linkage to the same chromosome 19 locus.
may not have neural degeneration and usually manifest other
neurological signs (especially parkinsonism), and exogenous or
environmental etiologies. Primary dystonia consists of at least MyoclonusDystonia Syndrome
5 autosomal dominant disorders, each having reduced pen- T. Gasser
etrance and variable expression. Clinically the primary dysto- Department of Neurology, Klinikum Grosshadern, Ludwig-
nias can be organized by the predominant family phenotype Maximilians-University Munich, Munich, Germany
into three groups, each having at least one associated genetic
locus: early limb-onset (DYT1), a mixed phenotype with early Myoclonusdystonia syndrome (MD) is an autosomal dom-
and adult onset dystonia usually involving cervical, cranial and inant disorder characterized by bilateral, alcohol-sensitive myo-
brachial muscles (DYT6 and 13), and adult-onset focal dysto- clonic jerks involving predominantly the arms, neck, and axial
nias (DYT7 and at least one other locus). A gene has been muscles and relatively mild dystonia (usually torticollis and/or
identified for only one of the PTD loci: TOR1A (at locus writers cramp) in some affected individuals. Onset of abnor-
DYT1). The clinical spectrum of TOR1A has been amplified in mal movements is usually in the first or second decade of life.
reports from many ethnically diverse populations and is gen- In addition to motor symptoms, patients often show psychiatric
erally consistent (with early limb-onset dystonia in most but not abnormalities, including panic attacks and obsessive
all). The range of dystonia, including the extent of body regions compulsive behavior and alcohol abuse. The disease has been
affected and severity of contractions, is quite variable both mapped to a locus on chromosome 7q21 by Nygaard and co-
within and among DYT1 families. Further, although dystonia is workers and this finding has been confirmed by several groups
expressed in only about 30 to 40% of TOR1A gene carriers, in at least 8 families, indicating that this appears to be the major
other features, including abnormal PET resting brain network locus responsible for this phenotype. Recently, we have iden-
patterns and motor sequence learning deficits, may be present
tified five different heterozygous loss-of-function mutations in
in non-dystonic gene carriers. The reasons for DYT1 variable
the gene for epsilon-sarcoglycan (SGCE) in six German fami-
expression and reduced penetrance remain unknown.
lies with MDS. This finding was surprising, as the four other
members of the sarcoglycan family of genes (, , , and
Genetics of DYT6, DYT7, DYT12, and DYT13 sarcoglycan) so far had been implicated only in autosomal-
L. Ozelius recessive limb girdle muscular dystrophies. The mechanism, by
Molecular Genetics Department, Albert Einstein College of which mutations in the SGCE-gene cause MDS is unknown.
Medicine, Bronx, New York, USA All mutations published so far are likely to lead to a loss of
protein function. In addition, the inheritance pattern of MDS
The DYT6 locus was identified by linkage analysis using indicates that inactivation of one parental allele may contribute
Swiss Mennonite families. The clinical picture is broad or to -sarcoglycan deficiency. Pedigree analysis in MDS-families
mixed with an early age of onset and progression to involve showed a marked difference in penetrance depending on the
multiple body regions. The DYT6 was mapped to a 40cM parental origin of the disease allele, with reduced penetrance
region on chromosome 8 with identical haplotypes segregating occurring predominantly if the disease allele is passed on by the
in both families, suggesting a common founder. Recent studies mother. This pattern is suggestive of a maternal imprinting
using additional polymorphic markers and a newly ascertained mechanism (i.e., inactivation of the maternally inherited allele,
branch of the family place the gene into a region of about 24.5 presumably by methylation) which has already been demon-
cM. Several large families with late-onset PTD have been de- strated in the mouse -sarcoglycan gene. This hypothesis is
scribed. One such family, from Northwest Germany, manifests supported by the observation, that the SGCE-gene is in fact
primarily late-onset focal cervical dystonia (torticollis). This differentially methylated in humans (M. Grabowski, unpub-
family was used for linkage studies and a gene, DYT7, local- lished results). Furthermore, preliminary rtPCR-experiments
ized to a 30 cM region on chromosome 18p. However, linkage indicate that only one parental allele appears to be preferen-
analyses in other clinically similar families have excluded tially expressed (A. Zimprich, unpublished observations).

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


Nondystonic Features of Hereditary Dystonia apparently sporadic cases, have shown GCH1 mutations. How-
R. Saunders-Pullman ever, no mutations in the coding region (including the splice
Beth Israel Medical Center, New York, New York, USA sites) of GCH1 were found in approximately 40% of DRD
families, using conventional genomic DNA sequencing of this
The penetrance of dystonia genes is incomplete: DYT1 is gene. Only several patients with DRD have been reported to
autosomal dominant with 30 to 40% penetrance. DYT5 is au- have TH mutations. Thus, because not all DRD patients have
tosomal dominant with 30% penetrance and female-to-male demonstrated mutations in the coding region of GCH1 or TH,
ratio of 23:1 and DYT11 is autosomal dominant with un- the present DNA testing for DRD is not suitable for routine
known reduced penetrance, and penetrance is increased with clinical practice. A therapeutic trial with levodopa is still the
paternal transmission. Penetrance is dependent on phenotype, most practical approach to the diagnosis of DRD. Neuropath-
however, and if our understanding of phenotype changes, in ological studies showed no Lewy bodies and a normal popu-
particular if non-dystonic features are also an expression of lation of cells with reduced melanin in the substantia nigra of 2
dystonia genes, then penetrance estimates also change. There patients with GTPCH-deficient DRD. There have been no re-
are many possible modifiers of dystonia genes, including en- ports of autopsied patients with TH-deficient DRD. Neuro-
vironmental, other epigenetic factors, gender and genetic modi- chemical data suggest that striatal dopamine reduction in
fiers. In evaluating secondary dystonia and DYT1, Bressman GTPCH-deficient DRD is caused not only by decreased TH
demonstrated that perinatal asphixia and neuroleptic use appear activity resulting from a low cofactor level but also by actual
not to be triggers for expression of DYT1, measles may be a loss of TH protein without nerve terminal loss. In GTPCH-
modifier, and the role of peripheral trauma is unclear. If early deficient DRD, striatal TH protein loss may be due to a dimin-
environmental modifiers play a role in expression of DYT1 ished regulatory effect of BH4 on the steady-state level of TH
they may alter neuronal plasticity in early childhood leading to molecules. Recent findings of only modest reduction of TH
decrease in torsin A to subthreshold levels during a vulnerable protein and dopamine despite marked reduction of total biop-
window. To test whether early childhood illness was associated terin (most exists as BH4) in the putamen of an asymptomatic
with manifesting DYT1, a self-administered standardized ques- GCH1 mutation carrier suggest that the extent of striatal TH
tionnaire was given to DYT1 family members studied, in whom protein loss may play a critical role in determining the symp-
gene status and neurological exam status was known. We found tomatic state of GTPCH-deficient DRD. Notwithstanding the
that earlier age of varicella, measles and fever greater than 1 discovery of GCH1 and TH mutations responsible for DRD,
week were associated with manifesting dystonia (P < 0.029, there remain many important unresolved issues regarding this
0.06, and 0.023, respectively) but not mumps (P < 0.078). treatable disorder, including questions of gender-related incom-
Therefore infection may influence penetrance and expression plete penetrance and intrafamilial phenotypic variation (e.g.,
of dystonia. DYT11 also has reduced penetrance, presumed adult-onset benign parkinsonism). A clarification of the
secondary to a mechanism of maternal imprinting, such that mechanism of striatal TH protein loss in GTPCH-deficient
transmission through the mother leads to inactivation of the DRD may provide a new clue to the pathogenesis of this major
allele and non-expression. However, this penetrance pattern is form of DRD.
incomplete with some individuals inheriting the maternal allele
expressing symptoms, and others with the paternal allele not
expressing. We previously demonstrated that obsessive Cloning of the Gene Defect Responsible for X-linked
compulsive disorder and alcohol abuse may be associated with DystoniaParkinsonism (XDP; lubag): Clinical and Patho-
carrying the DYT11 gene, and therefore may be part of the logical Aspects of X-linked DystoniaParkinsonism
phenotypic spectrum of DYT11. In three families studied, we A. Singleton
found that broadening the phenotype to include any psychiatric National Institutes of Health, Bethesda, Maryland, USA
features did not improve sensitivity and specificity of the im-
printing model, however limiting to obsessivecompulsive dis- XDP is believed to originate ancestrally from the Filipino
order and alcohol dependence did. Therefore, better under- island of Panay, the mean age of onset of symptoms in Lubag
standing the phenotypic spectrum may improve our under- is 35 years, with cases reported from the age of 12 to 48 years
standing of penetrance. 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
Dopa-Responsive Dystonia or generalized dystonia. In addition a common characteristic of
Y. Furukawa the disease is the presence of Parkinsonian features (40% of
Movement Disorders Research Laboratory, Centre for Addic- cases examined). We have performed haplotype analysis on 50
tion and Mental Health-Clarke Division, Toronto, Ontario, affected individuals, their nuclear families and controls. A co-
Canada segregating haplotype has been found in all cases to date. We
have failed to demonstrate the flanking recombinant events at
Dopa-responsive dystonia (DRD) is a syndrome character- DXS559 and DXS6673E 3shown previously and thus our seg-
ized by childhood-onset dystonia and a dramatic and sustained regating region is approximately 200-kb larger. We have se-
response to low doses of levodopa. There are two known types quenced the coding region of all of the known genes within the
of DRD: autosomal dominant GTP cyclohydrolase I (GTPCH)- critical region including ZNF261, p54nrb, OGT, CCG1, CKR-
deficient DRD caused by GCH1 mutations and autosomal re- L2, melusin, NAAR1, and GJP-1B. We amplified the full-
cessive tyrosine hydroxylase (TH)-deficient DRD due to TH length cDNAs from ZNF261, CCG1, OGT, melusin, p54nrb
mutations (the mild form of TH deficiency). GTPCH catalyzes and CKR-L2 in an adult and fetal cDNA library and in lym-
the first step in the biosynthesis of tetrahydrobiopterin (BH4; phocyte DNA from an XDP case, his mother and an unrelated
the essential cofactor for TH). Many DRD patients, including control. We have performed northern blot analysis of these

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


genes on RNA from a case and a control. No alterations in blepharospasm. Allele 2 was found to be positively associated
coding sequence, splicing or expression have been found to with both conditions and allele 6 was significantly more fre-
date. 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
A Novel DDP Gene Mutation that Causes Dystonia in Fe- with an allele in the D5 receptor gene may indicate a patho-
male Carriers of the Mohr-Tranebjaerg Syndrome. genic or susceptibilty role of this gene. It is known that D5
R.H. Swerdlow, V.C. Juel, and G.F. Wooten receptor gene mRNA is expressed in the substantia nigra pars
Department of Neurology, University of Virginia Health Sys- compacta supporting the hypothesis that a functional varient of
tem, Charlottesville, Virginia, USA the D5 receptor could influence basal ganglia dopaminergic
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 Mutation Analysis of the Epsilon-Sarcoglycan Gene in 15
now describe a novel guanine deletion at nucleotide 108 of the Families with MyoclonusDystonia
DDP gene in a family with X-linked male deafness and dysto- P. de Carvalho Aguiar,1,2 L. Liu,1 N. Kock,3,4 B. Mueller,3,4 D.
nia, which terminates this 97 amino acid protein at codon 25. Raymond,5 J. Harris,6 D. Doheny,7 S. Frucht,6 B. Ford,6 T.
Unlike previously reported kindreds, carrier females in this Lynch,6 D. deLeon,5 J. Garrels,3,4 E. Schwinger,4 M. Brin,7 R.
family also manifest dystonias, including torticollis and writ- Kurlan,8 A. Lang,9 S. Fahn,6 R. Saunders-Pullman,5 V.
ers cramp. Female carriers do not, however, manifest hearing Borges,2 H.B. Ferraz,2 J. Friedman,10 S. Fahn,6 C. Klein,3,4 S.
loss. A family history of male deafness should alert clinicians Bressman,5 L. Ozelius1
to the possibility of DDP mutation in women with focal dys- Molecular Genetics Department, Albert Einstein College of
tonias. As DDP is a translocator of the inner mitochondrial Medicine, New York, New York, USA; 2Department of Neurol-
membrane and plays a role in mitochondrial protein import, ogy and Neurosurgery, Federal University of So Paulo, So
genetic studies of sporadic dystonia should consider the Paulo, Brazil; Departments of 3Neurology and 4Human Genet-
broader family of mitochondrial translocase peptides. 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,
Two Forms of Focal Dystonia are Associated with Polymor- New York, New York, USA; 7Department of Neurology, Mount
phisms in the Dopamine-5 Receptor Gene Sinai School of Medicine, New York, New York, USA; 8Depart-
A. Misbahuddin,1 M. Placzek,1 K. Bhatia,2 K. Ray Chaudhuri,3 ment of Neurology, University of Rochester School of Medi-
N. Wood,2 T.T. Warner1,2 cine, Rochester, New York, USA; 9Division of Neurology, De-
Department of Clinical Neuroscience, Royal Free and Uni- partment of Medicine, University of Toronto and the Toronto
versity College Medical School, London; 2Institute of Neurol- Western Hospital, Toronto, Ontario, Canada; 10Department of
ogy, London; 3Kings College Hospital, London, United King- Neurology, Massachusetts General Hospital, Boston, Massa-
dom chusetts, USA

Background: There is increasing evidence that dystonic Discovery of the causative gene revealed broadness of phe-
movements may be the result of abnormal dopamine neuro- notypical variation of HPD/DRD. It had been shown that the
transmission in the cortico-motor basal ganglia circuits. Genes rates of mutant /wild type GCH-1 in RNA in lymphocytes vary
causing generalized primary torsion dystonia (DYT1) and in one mutation and differ depending on the locus of mutation
dopa-responsive dystonia (GTP-cyclohydrolase 1) appear to ef- [Hirano et al., Ann Neurol 1998;44:365371]. Thus, we as-
fect nigral dopaminergic function. Dopamine receptor blocking sessed the incidence of familial occurrence, interfamilial varia-
drugs are well known to cause tardive dystonia, and dystonic tion of symptoms and presence of atypical phenotypes in fami-
movements can be produced in primates treated with the nigral lies of gene-proved HPD/DRD and evaluated their correlation
toxin MPTP. In addition a SPECT study showed evidence of to the loci of mutations. In atypical phenotypes we included
decreased striatal D2 receptor binding in cases of cervical dys- dystonic cramp, axial torsion, spontaneous remission, occulo-
tonia (CD). Focal dystonia is the commonest form, and most gyric crisis, action dystonia, focal dystonia and early onset in
cases appear to be sporadic although there are some families infancy with delay in motor milestones. Fifty-one families, in-
with clear autosomal dominant inheritance pattern. The precise cluding 13 personal ones with precise description of clinical
cause of focal dystonia is unknown. Objectives: To assess symptoms and the pedigree were subjected to this study. Pa-
whether polymorphisms in the dopamine receptor and trans- tients with compound heterozygotes were excluded from this
porter genes are associated with development of sporadic CD study. Of them 46 had mutations in coding regions, 20 in exon
or blepharospasm. Methods: A case control allelic association 1, 7 in exon 2, 1 in exon 3, 4 in exon 4, 7 in exon 5 and 7 in
study of 100 patients with CD and 90 patients with blepharo- exon 6 and 5 in introns, one in intron 1, 2 each in intron 2 and
spasm and control groups of 100 individuals using polymor- 3. Seventeen of 51 families had familial occurrence. In personal
phisms within the D1-5 receptor and dopamine transporter families, it was 5 out of 13; 2/4 in exon 1, 1/2 in exon 2, 0/2 in
gene. Results: No association was found between patient and exon 4, 1/2 in exon 5, 1/1 in exon 6 and none of 3 families with
control polymorphism allele frequency for D1-4 receptors and mutation in intron. They were 10/20 in exon 1, 5/7 in exon 2,
dopamine transporter. However significant results were ob- 1/1 in exon 3, 1/4 in exon 4, 3/7 in exon 5 and 6/7 in exon 6.
tained with the D5 receptor microsatellite for both CD and Among families with mutation in intron one in intron 3 had

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


familial occurrence. As for intrafamilial variation, mild antici- family did not identify any changes in nucleotide sequence
pation was observed in families with mutation in the exon 1 and compared to healthy controls. This indicates that RDP in these
marked variation without any relation to the generation in fami- families is not caused by mutations in either exons 219 or in
lies with abnormalities in exon 5 and 6. As for the phenotypes a putative negative regulatory region within intron 1 of the
shown after the discovery of the gene dystonic cramp and toti- GRIK5 gene.
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
Sporadic and Familial Primary Torsion Dystonia Cases in
observed in those with mutation in the exon 6. Delay in devel-
opmental motor milestones with hypotonia and abnormalities A. Elia,1 E. Lo Schiavo,1 E. Cassetta,1,2 T. Ialongo,1 E.M.
in locomotion, as well as occulogyric crisis observed in patients Valente,1,3 A.R. Bentivoglio,1 A. Albanese1,4
with compound heterozygote may be due to hypofunction of 1
Istituto di Neurologia, Universit Cattolica, Rome; 2Ospedale
the serotonergic neurons caused by marked reduction of the Fatebenefratelli, Rome; 3Istituto Mendel, Rome; 4Istituto Na-
tetrahydrobiopterin (BH4). DYT-1 has two phenotypes depend- zionale Neurologico, Milan, Italy
ing on families, one is postural dystonia and the other is action
The Gemelli dystonia registry encompasses 593 cases of
dystonia and the upper generation of the latter has patients with
dystonia out of a series of 4581 patients with movement dis-
focal dystonia. These suggest phenotypical variation depend on
orders. They originate from all Italian regions, but the majority
the grade of reaction of BH4 and/or difference of the involved is from Central and Southern Italy. Familial and sporadic pri-
neuronal pathways, both of which might depend on the varia- mary torsion dystonia (PTD) cases were grouped based on
tion of gene abnormalities. Thus, these results imply that the phenotype. Genetic analysis was performed using currently
each loci of GCH-1 gene has particular modulation in the pteri- available techniques. 460 PTD patients (296 women, 164 men)
din metabolism and affect particular NS-DA neurons and path- were followed up for an average of 2.4 3.2 years. Their mean
ways of the basal ganglia which is involved in pathophysiolo- age at onset was 48.3 17.7; disease duration was 13.7 9.0
gies for various types of dystonia. 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
Evaluation of GRIK5 (KA2) as a Candidate Gene for for cervical, 1:2 for lower-limb PTD). In addition, the mean age
Rapid-Onset DystoniaParkinsonism (RDP, DYT12) at disease onset was higher in women in the focal forms listed.
C. Kamm,1 J. Leung,1 A. Brashear,2 W. Dobyns,3 X. Break- By contrast, upper limb PTD had a higher incidence in men
efield,1 L. Ozelius4 (male-to-female ratio 2.2:1) and also a higher age at onset in
Molecular Neurogenetics Unit, Massachusetts General Hos- men. At last visit, 269 PTD patients were still affected by focal
pital, and Department of Neurology and Genetics and Neuro- dystonia, 159 by segmental dystonia, 7 by multifocal dystonia
science Program, Harvard Medical School, Boston, Massachu- and 25 by generalized dystonia. In all, 41.5% had clinical pro-
setts; 2Department of Neurology, Indiana University School of gression. When comparing patients grouped by body district
Medicine, Indianapolis, Indiana; 3Department of Human Ge- affected at onset. A clinical progression was found in PTD
netics, Neurology and Pediatrics, University of Chicago, Illi- cases with cranial onset (41.1%), cervical (45.3%), upper limb
nois; 4Department of Molecular Genetics, Albert Einstein Col- (29.6%), or lower limb onset (75%). Familial aggregation was
lege of Medicine, Bronx, New York, USA 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
Rapid-onset dystoniaparkinsonism (RDP) is a rare autoso- prevalently focal phenotype, 16 a prevalently segmental, and 8
mal dominant movement disorder characterized by abrupt onset a generalized phenotype. Age of onset was juvenile in all fami-
of persistent dystonia and parkinsonism, generally during late lies with generalized PTD and adult in the other ones. Twenty-
childhood or early adulthood, with little or no progression two family probands were tested for DYT1 mutation and 3 of
thereafter. Recently, linkage of this disease to an 8cM region on these resulted carriers of GAG deletion of DYT1 gene: all
chromosome 19q13 (DYT12) has been reported. One of the presented generalized dystonia with early limb-onset and rapid
candidate genes in this region, GRIK5, encodes a kainate-type generalization. No DYT1 patient carried the novel 18-bp dele-
tion. The prevalent (20.1% of families) phenotype of non-
glutamate receptor subunit, KA2. In rat brain, KA2 mRNA is
DYT1 familial cases was cranial-cervical dystonia with occa-
expressed at high levels in the basal ganglia, especially in the
sional limb dystonia (cranial-cervicalplus dystonia). Isolated
striatum, substantia nigra pars compacta and subthalamic cranial-cervical dystonia was found in 16.5% of familial cases,
nucleus, regions that are critically involved in movement con- focal cervical dystonia in 5.5%, cervical dystonia with limb
trol. Given that corticostriatal glutamatergic neurons form the involvement (cervical-plus dystonia) in 17.4%, Meiges syn-
major afferent projection to the striatum, the KA2 subunit could drome in 4.6%, blepharospasm in 7.3%, laryngeal dystonia in
act by modulating dopaminergic input into the striatum. There- 8.2% and writers cramp in 3.6%. Generalized dystonia oc-
fore, in order to evaluate the role of this gene in rapid-onset curred in 16.5% of familial cases and mioclonic dystonia in
dystoniaparkinsonism, we performed mutational analysis in 5.5%. Focal oromandibular or lower limb dystonia did not rep-
two previously described RDP families with linkage to 19q13. resent a phenotype observed in familial aggregation. The
Screening of GRIK5 exons 219 and a 300-bp region within cervical-plus group included a large family with 11 affected
intron 1, which has previously been shown to downregulate members linked to a novel PTD locus (DYT13) located on
expression of the rat GRIK5 gene, in 2 patients from each chromosome 1p36.13-36.32.

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


A Screen of GTP Cyclohydrolase I in Parkinsons Disease Sequencing Strategies to Identify Segregating Alterations in
Patients X-Linked DystoniaParkinsonism
C. Evey,1 M. Hanson,1 A. Singleton,2 K. Gwinn-Hardy,2 M. S. Hague, D. Hernandez, J. Hardy, A. Singleton
Farrer,3 A. Singleton4 Laboratory of Neurogenetics, National Institute on Aging, NIH,
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA
NIH, Bethesda, Maryland; 2Neurogenetics Branch, National The X-linked recessive dystoniaparkinsonism syndrome
Institute of Neurological Disorders and Stroke, NIH, Bethesda, (XDP) is a severe progressive disease presenting with focal
Maryland; 3Mayo Clinic Jacksonville, Jacksonville, FL; dystonia, progressing to a generalized form with concomitant
Laboratory of Neurogenetics, National Institute on Aging, parkinsonism in 50% of cases. XDP originated from a common
NIH, Bethesda, Maryland, USA ancestor in the Filipino population and is particularly prevalent
on the Philippine island of Panay. XDP is inherited in an
Dopa-responsive dystonia (DRD), mapped to chromosome X-linked recessive manner, consequently the vast majority of
14q22.1-q22.2, is associated with mutations of the GTP cyclo- cases are male. Linkage and allelic association studies have
hydrolase I (GCH-I) gene. GCH-I is the rate-limiting enzyme in assigned the gene to a 350kb interval on the X chromosome
the synthesis of tetrahydrobiopterin (BH4), which is required residing to the Xq13.1 region between the markers DXS6673E
for the synthesis of L-dopa by tyrosine hydroxylase (TH). DRD, and DXS559, a region of approximately 350 kb. Intense efforts
both an autosomal dominant and recessive disorder, is charac- to clone the defective gene have proved difficult. The exons
terized by childhood or adolescent onset of dystonia sometimes and introns of a number of genes residing in this critical region
associated with parkinsonism, and response dramatically to low have been sequenced and as yet no causative mutation has been
doses of L-dopa. Presently, up to 60 mutations in GCH-I have detected. Additionally, the upstream regulatory regions of these
been reported in DRD patients. It has been demonstrated that a genes have been sequenced and no mutations detected. In an
single heterozygotic mutation in GCH-I may result in less than attempt to identify the mutation responsible for XDP we have
50% of normal activity via a postulated dominant-negative produced a Cosmid library from an XDP affected male. The
mechanism. This decrease of GCH-I activity may lead to di- library contains the 350 kb critical region and additional up-
minished dopamine production, which could then result in stream and downstream sequence. The cosmid library has been
clinical manifestations of DRD. Furthering this concept, abnor- shotgun cloned into a plasmid vector and is presently being
malities in GCH-I may also help to explain the cause of other sequenced and a contig of the entire region constructed. Elu-
neurodegenerative disorders that result from dopamine defi- cidation of the causative genetic defect in XDP will not only
provide a therapeutic target for the treatment of this disease but
ciency, such as Parkinsons disease. Thus, we have undertaken
will provide an insight into the mechanisms involved in other
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. Identification and Screening of Candidate Genes Within
the X-linked Recessive DystoniaParkinsonism Critical
Spinal Cerebellar Ataxia 8 Presenting with Dystonia D.G. Hernandez,1 V. Evidente,2 A. Jhoe-Anthony,3 F. Nativi-
S. Gauthier and M. Saint-Hilaire dad,3 J. Hardy,1 A. Singleton1
Boston University Medical Center, Boston, Massachusetts, 1
Laboratory of Neurogenetics, National Institute on Aging,
USA NIH, Bethesda, Maryland, USA; 2Mayo Clinic, Scottsdale, Ari-
zona, USA; 3St Lukes Hospital, Quezon City, The Philippines
The spinal cerebellar ataxias are a heterogeneous group of
disorders that are distinct syndromes classified by their genetic Background: X-linked dystoniaparkinsonism (XDP) is a re-
locus. The original description of the spinal cerebellar ataxia 8 cessively inherited, severe, adult-onset movement disorder. It is
phenotype included spastic and ataxic dysarthria, nystagmus, characterized by dystonia, predominantly focal at presentation,
limb and gait ataxia, limb spasticity, and diminished vibration progressing to a generalized form with co-incidental parkin-
perception. Case reports following the original description, re- sonism in about 50% of the cases. XDP is believed to originate
mained with a predominant syndrome of pyramidal tract in- from a common ancestor in the Philippine island of Panay.
Linkage and allelic association studies have mapped the gene
volvement, ataxia, and a mild axonal neuropathy. Extrapyra-
defect causing this disorder to a small interval in Xq13.1. This
midal involvement has not been described to be a main feature
interval of approximately 300kb is flanked by the markers
of spinal cerebellar ataxia 8 in any families studied. The only DXS6673E and DXS559. Objective: To identify the disease
previously reported extrapyramidal symptoms were mild ath- causing mutation within the XDP critical region, and to pro-
etotic movements of the fingers in 4 patients of a seven- duce a comprehensive physical map of the candidate region
generation family. We report on a patient with a neck dystonia associated with XDP to facilitate identification and analysis of
as a novel presentation for spinal cerebellar ataxia 8. His symp- all candidate genes. Methods: We have performed haplotype
toms began at the age of 28 with episodic head twitching and analysis on affected individuals, their nuclear families and con-
dysarthria. These symptoms progressed over an 8-year period, trols. We have used an electronic database mining and posi-
at which time, he was found to have limb ataxia. On examina- tional cloning strategy to identify genes within the critical re-
tion, the patient had intermittent turning of his head to the right, gion and have constructed a physical map of the candidate
dysarthria, and limb ataxia. After an extensive workup, he was region using a series of BACs, PACs and cosmids. We have
found to have 135 CTA/CTG repeats for the SCA8 mutation. sequenced all eight genes in XDP cases and their mothers.

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


Additionally, we have sequenced the coding exons of one gene Like tottering mice, the motor attacks in lethargic mice have a
centromeric to the candidate region, gap junction protein 1b predominantly dystonic morphology. However, other features
(GJP 1b). We have examined full-length gene transcripts from of the attacks in lethargic mice are quite distinct from those of
all eight genes amplified in adult and fetal cDNA libraries, tottering mice. Attacks in lethargic mice are triggered by ex-
lymphocyte DNA from both an XDP case and his mother and ercise or caffeine, occur hundreds of times per day, and last
an unrelated control. Results: Although a co-segregating hap- only between 4 and 8 minutes. Even when performed by a
lotype has been found in all cases to date, we have yet to blinded observer, the quantitative methods were readily capable
demonstrate the flanking recombinants at DXS559 and of discriminating between the two genotypes. Quantitative
DXS6673E3 previously reported by Nemeth et al. In addition EEG revealed frequent 6 Hz polyspike discharges in both of the
to identifying previously mapped genes, we have examined mutants. However, their motor attacks were not associated with
four more full-length genes within the critical region, melusin, any change in the frequency of these polyspike discharges or
FLJ23071, CKR-L2 and Neuroligin 3 (NLGN3.) We have yet the power spectrum. The phenomenology and lack of EEG
to find any coding changes within these genes that segregate correlates confirm that the motor attacks in tottering and le-
with disease; however, we have identified a polymorphism in thargic mice reflect paroxysmal dyskinesia rather than motor
the Neuroligin 3 gene that segregates with diesease in all XDP epilepsy. These studies demonstrate paroxysmal dyskinesias in
cases. We have examined a large number of XDP patients in mice to result from a channelopathy affecting P/Q-type calcium
order to define the minimal segregating haplotype. We have channels. These mice provide valuable new tools to investigate
sequenced known and novel genes within the candidate region the pathophysiology of the paroxysmal dyskinesias and raise
but have not found a segregating mutation. In addition to iden- the possibility that paroxysmal dyskinesias in humans may re-
tifying and sequencing the promoter regions of each gene, we flect also dysfunction of ion channels. [Note: This work was
are currently utilizing a number of strategies aimed at identi- supported by the National Institutes of Health (NS40470 and
fying new genes in and around the candidate region. NS33592).]

Novel Animal Models for Paroxysmal Dystonia Is Phenotypic Variation of Hereditary Progressive Dystonia
H.A. Jinnah, Z. Khan, L. Rao, M.Y. Shin, B.E. Fureman, E.J. with Marked Diurnal Fluctuation/Dopa-Responsive Dysto-
Hess nia Caused by Difference of the Locus of Mutation on the
Johns Hopkins Hospital, Baltimore, Maryland, USA GTP Cyclohydorolase 1 Gene?
The paroxysmal dyskinesias include a rare group of disor- M. Segawa,1 S. Yukishita,1 K. Hoshino,1 K. Hachimori,1 Y.
ders characterized by intermittent attacks of involuntary abnor- Nomura,1 N. Nishiyama,2 H. Ichinose,3 M. Yokochi4
mal movements unassociated with any epileptiform activity in Segawa Neurological Clinic for Children, Tokyo; 2Gradu-
EEG recordings. The movements are often dystonic or chorei- ate School of Pharmaceutical Sciences, University of Tokyo, Tokyo;
form, but may include a variety of other abnormalities. The Institute for Comprehensive Medical Science, Fujita Health Univer-
paroxysmal dyskinesias are currently divided into three groups, sity, Toyoake, Aichi; 4Department of Neurology, Tokyo Metropolitan
based on triggers of attacks, attacks duration, predominant mor- Ebara Hospital, Tokyo, Japan
phology, and other features. The pathophysiology of this un- There are broad phenotypic variations in HPD/DRD. The
usual group of disorders is currently not well understood. Ani- ratio of mutant to wild-type mRNA of GCH-1 varies in one
mal models can provide valuable tools to investigate the patho- mutation and differ depending on the locus of mutation. Thus,
physiology of human disease. The only well-described animal we assessed the incidence of familial occurrence, inter-and
model for paroxysmal dyskinesia is an inbred line of golden intra-familial variation of symptoms and atypical phenotypes in
Syrian hamsters, which display predominantly dystonic dyski- families of gene-proved HPD/DRD and correlated them to the
nesias in response to stress and other influences. The cause of mutation loci. Evaluated atypical phenotypes were dystonic
paroxysmal dyskinesias in these hamsters remains unknown. In cramp, oculogyric crisis, action dystonia, focal dystonia, delay
recent studies, we identified the existence of paroxysmal dys- in motor milestones and spontaneous remission. Sixteen fami-
kinesias in two strains of mice, each carrying a defined muta- lies with 32 patients (27 women, 5 men) personally examined
tion affecting voltage-regulated calcium channels. As the first were subjected to this study. Six families had mutations in exon
step in characterizing the paroxysmal dyskinesias in these mice, 1, 2 in exon 2, 2 in intron 3, 2 in exon 4, 1 in intron 4, 2 in exon
we developed quantitative methods for measuring the fre- 5 and 1 in exon 6. Onset years slightly differed among muta-
quency, morphology, and severity of the attacks. We also per- tions; 6.1 2.4 in exon 1, 6.4 3.1 in exon 2 and 7.7 2.1 in
formed digital videotaping and telemetry to quantify cortical exon5. One patient with mutation in intron 3 had onset at 58
EEG changes associated with attacks in freely moving animals. years, the other 4 had onset at 6.6 2.6. One each in intron 4
The tottering mouse carries a point mutation in the CACNA1A and exon 6 developed the symptoms at 13 and 7 years, respec-
gene, which encodes the pore-forming subunit of brain P/Q- tively. Eleven families had familial cases. Anticipation was
type calcium channels. These mice display absence epilepsy, observed in symptomatic cases in 5 families; 2 in exon 1 and
mild ataxia, and intermittent attacks of severely disabling motor one each in exon 2, intron 3 and intron 4. Marked intra-familial
dysfunction. The motor attacks can be reliably triggered by variation in the grade of symptoms was observed in a family of
stress or caffeine, occur several times per day, last 40 to 60 exon 5. There were 5 sporadic cases: two in exon 1 (including
minutes, and have a predominantly dystonic morphology. The one de novo case), 2 in exon 4 and one in exon 6. Dystonic
lethargic mouse carries an insertion mutation in the CACNB4 cramp was observed in 5 (3 in exon 1, one each in exon 2 and
gene, which encodes the -4 subunit of brain P/Q-type calcium 5), action dystonia in 4; one with oculogyric crisis in intron 3,
channels. These mice display absence epilepsy, mild ataxia, 2 in exon 2 and one in exon 6. Torticollis was observed in 4
hypokinetic motor behavior, and intermittent motor attacks. (one each in exon 1, 2, 6 and intron 4). One in exon 5 had

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


spontaneous alleviation in the puberty. Levodopa induced dys- and network analysis. Results: NM-DYT1 did not differ from
kinesia in a female (T.O.), an elder sister of a patient with controls in MCCW: spatial and timing errors and motor acti-
mutation in exon 1. No patient showed delay in development of vation responses were similar for the two groups. During
motor milestones. All examined patients had characteristics of MSEQ, learning performance (GL) was reduced in the NM-
HPD/DRD basically. Minor variations, started with arm dys- DYT1 group (P < 0.01). This was associated with a relative
tonia or hand tremor were observed in patients with ages at increase (P 0.01) in the activation of the left prefrontal
onset over 8 years. No patients showed tremor in their clinical cortex (BA 11), right anterior putamen and the lateral cerebel-
course if levodopa was administered before this age. Thus there lum in the gene carriers. In normal subjects performing MSEQ,
are age-related variations. Dystonic cramp as well as torticollis GL is highly correlated with the activity of a specific brain
was observed together with action dystonia. Two patients, 1 network involving DLPFC, PMC, and posterior parietal re-
with oculogyric crisis with mutation in intron 3 and the other in gions. However in NM-DYT1 carriers, learning performance
exon 6 were shown to have a different pathophysiology than did not correlate (R2 0.09, P 0.3) with the activity of this
classical HPD/DRD by the polysomnographyies. Thus, action network. By contrast, in these subjects GL correlated signifi-
dystonia as well as dystonic cramp and torticollis may be phe- cantly (R2 0.47, P 0.006) with the activity of a different
notypic variation related to the loci of mutation. The case T.O. network involving the striatum and ventral prefrontal cortex.
reported by Narabayashi and Yokochi had similar neurohisto- Conclusions: In NM-DYT1 carriers, motor sequence learning is
chemical findings as HPD/DRD, but with some neruopatho- associated with relative activation of brain regions normally
logical findings suggesting pathology of Parkinsons disease. mediating the earliest phases of this process. Abnormal transfer
She as well as her brother had clinical characteristics similar to from frontal to posterior parietal cortical areas may be the basis
HPD/DRD. The particular neuropathological changes might be for the impairment in learning that was observed in these sub-
caused by huge dosis of levodopa. jects. [Note: This work was supported by the National Institutes
of Health (RO1 NS 37564) and the Dystonia Medical Research


CHEMISTRY OF DYSTONIA Dysfunction of Dopaminergic Pathways in Dystonia
J.S. Perlmutter
Washington University School of Medicine, St. Louis, Missouri,
Abnormal Brain Function in Nonmanifesting DYT1
Carriers Multiple neuroimaging studies indicate that dysfunction of
D. Eidelberg and M. Carbon dopaminergic pathways contributes to the pathophysiology of
Center for Neurosciences, North Shore-LIJ Research Institute, dystonia. Early structural imaging studies identified lenticular
New York University School of Medicine, Manhasset, New nuclei and other brain regions as sites of pathology in second-
York, USA ary dystonias. Later, imaging studies with positron emission
tomography (PET) and functional magnetic resonance demon-
Background: In an earlier metabolic PET study we identified strated dysfunction in putamen and cortical-basal ganglia cir-
an abnormal resting metabolic brain network in neurologically cuits including specific abnormalities of dopaminergic path-
normal NM-DYT1. We have previously reported abnormalities ways. These findings fit well with recent observations of re-
in sequence learning in NM-DYT1. In normals performing se- duced cortical inhibition in people with dystonia. Structural
quence learning tasks, target acquisition is associated with ac- abnormalities have been found in the basal ganglia contralateral
tivation of the striatum, DLPFC, preSMA, and anterior cingu- to the symptomatic side in hemidystonic patients. The putamen
late; target retrieval is associated with activation of the premo- has been the most common site of such lesions in secondary
tor cortex, the precuneus, and the right posterior parietal cortex. dystonias, and volumetric analyses revealed about a 10% in-
In this study, we scanned NM-DYT1 subjects with H215O/PET creased volume of putamen in those affected by primary cranial
to determine whether abnormal activation of these regions is or hand dystonia. PET measurements of regional cerebral blood
the basis for the sequence learning abnormality. Objective: To flow or metabolism either at rest or during activation have
use PET to determine the basis for abnormal motor sequence provided key insights into the pathophysiology of dystonia.
learning in non-manifesting carriers of the DYT1 mutation Resting-state studies have identified abnormal function of pu-
(NM-DYT1). Methods: 7 right-handed NM-DYT1 (age 50.8 tamen in people with primary and secondary forms of dystonia,
13.2 years) and 7 age-matched normal controls were scanned as well as alterations in function at other sites in cortical basal
while moving their dominant hand on a digitizing tablet at 1 ganglia motor circuits. Activation studies have identified dys-
Hz. All subjects performed two kinematically controlled motor function in sensory motor processing in dystonia and alter-
tasks:1.Motor execution (MCCW): paced reaching movements ations in brain activity during motor tasks that may be restored
toward 8 radially displayed targets were presented in a predict- to normal after dopaminergic drugs. Primary and some second-
able counterclockwise order; and 2.Motor sequence learning ary forms of dystonia may be associated with reduced activity
(MSEQ): the targets were presented in a repeating pattern. of presynaptic dopaminergic nigrostriatal neurons, as found
Subjects were explicitly required to synchronize target acqui- with[18F]fluorodopa (FD) PET. Decreased putamenal uptake of
sition with the tone, thus encouraging sequence learning and FD may occur in primary dystonias, but there is normal uptake
anticipation of the correct target. Performance was quantified in dopa-responsive dystonia despite deficient tyrosine hydrox-
as a global learning index (GL) defined as the total number of ylase activity. PET measurements of radiolabeled dopaminer-
correct anticipatory movements in each PET trial block. Acti- gic ligands have provided additional insights into the function
vation patterns were compared between groups using SPM99 of dopaminergic pathways in dystonia. Nonhuman primates

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


treated with intracarotid MPTP developed transient hemidys- of basal ganglia output. Multiple chemical signals and receptors
tonia prior to hemiparkinsonism. The dystonic phase corre- mediate or modulate the interconnecting pathways by which
sponded temporally with a decreased striatal dopamine content these abnormalities are mediated. They, thus, represent poten-
(9798%) and a transient decrease in D2-like receptor number tial targets for therapeutic manipulation. In primate models, we
(about 30% decrease) in putamen. Patients with cranial or hand have demonstrated that L-dopainduced dystonia can be alle-
dystonia also had a similar reduction of binding (29% decrease) viated by administration of: (1) -opioid receptor antagonists;
of [18F]spiperone in putamen These findings have now been (2) histamine H3 receptor agonists; (3) 2 adrenergic receptor
replicated in a similar group as well as in those with cervical antagonists; (4) cannabinoid receptor antagonists; and (5)
dystonia. In summary, there is substantial evidence that dopa- -opioid receptor antagonists. A key component of the neural
minergic pathways are implicated in the pathophysiology of mechanism underlying L-dopainduced dystonia is enhanced
dystonia. PET measures of dopaminergic receptor binding in synthesis of the opioid precursor preproenkephalin B (PPE-B)
people with dystonia and in an animal model with transient by the direct striatal output pathway. It is proposed that en-
dystonia suggest that this involvement may preferentially affect hanced stimulation of opioid receptors by the products of
D2-mediated pathways, which implicates the indirect pathway PPE-B is responsible for the generation of dystonia. Indeed, in
of the basal ganglia motor circuit. One primary function of monkeys with dystonia, there is a down-regulation of opioid
indirect pathway may be to broadly inhibit unwanted move- receptors in the output regions of the basal ganglia suggesting
ment during an intended movement. Conceivably, signal pro- enhanced receptor stimulation. In the MPTP-lesioned primate,
cessing through the indirect pathway could be influenced at opioid receptor antagonists alleviate L-dopainduced dysto-
many different points. Regardless of the site of primary pathol- nia. Histamine H3 receptor agonists: A key component of the
ogy, we hypothesize that dysfunction of the indirect pathway neural mechanism underlying dystonia is enhanced GABAer-
could lead to the loss of lateral cortical inhibition and abnormal gic inhibition of basal ganglia outputs by the direct pathway.
central sensory processing. The normalization of the vibration- H3 receptor stimulation can reduce GABA release in these
induced blood flow response in the dopa-responsive dystonia is structures. H3 receptor stimulation alleviates L-dopainduced
suggestive, but not proof, of this notion. Additional studies dystonia in MPTP-lesioned monkeys. Alpha 2 adrenergic re-
measuring the function of the direct pathway through the basal ceptor antagonists: As outlined above, a key component of the
ganglia will help clarify its role. Development and application neural mechanism underlying dystonia is enhanced transmis-
of new imaging tools may help address these unsettled issues, sion in the direct pathway. Alpha 2 adrenergic receptors appear
providing new insights into the pathophysiology of dystonia. 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-
Functional Anatomy and Pharmacology of Animal Models ade of 2 adrenergic receptors alleviates L-dopainduced hy-
of Dystonia perlocomotion, induced by stimulation of the direct pathway, in
A.R. Crossman rats and both chorea and dystonia, in MPTP-lesioned monkeys.
Division of Neuroscience, School of Biological Sciences, Uni- Cannabinoid receptor antagonists: The globus pallidus contains
versity of Manchester, Manchester, and Motac Neuroscience the highest levels of endogenous cannabinoids and cannabinoid
Ltd., Manchester, United Kingdom CB1 receptors of any brain region. We have shown that CB1
In Parkinsons disease, treatment with levodopa (L-dopa) or receptor stimulation can enhance GABA transmission by re-
dopamine agonists leads to the development of abnormal in- ducing GABA uptake in basal ganglia output regions. We have
voluntary movements (dyskinesias), of which dystonia may be also shown that L-dopainduced dystonia is reduced by the
a major component. In fact, L-dopainduced dystonia remains CB1 antagonist SR141716A in MPTP-lesioned monkeys.
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 V. MUSICIANS, AND OTHER FOCAL DYSTONIAS
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- Focal Task-Specific Dystonia in Musicians
tations of dystonia. There is strong evidence that the neural S. Frucht
mechanisms underlying L-dopainduced, and other forms of, The Neurological Institute, Columbia-Presbyterian Medical
dystonia involve abnormal patterns of activity in the efferent Center, New York, New York, USA
neurones of the striatum. These inhibitory, GABAergic, neu-
rones control the output of the basal ganglia, namely the medial Between 5 and 10% of patients seen at performing arts medi-
segment of the globus pallidus (GPm) and the substantia nigra, cine clinics are afflicted with focal task-specific dystonia,
pars reticulata (SNr). There are two principle types of striatal (FTSD), although the true incidence and prevalence of the con-
efferents. The so-called direct pathway projects directly to dition are unknown. FTSD has been reported in string (violin,
GPm and SNr output neurones. The indirect pathway con- viola, cello), keyboard (piano, accordion, organ, harpsichord),
trols basal ganglia output via the intermediary of the lateral plectrum (guitar, banjo, lute, mandolin), woodwind (flute, clari-
segment of the globus pallidus (GPl), which in turn inhibits the net, saxophone, oboe, bassoon) and brass players (trumpet,
subthalamic nucleus (STN). The STN is the major excitatory French horn, trombone and tuba). Symptoms usually begin in
drive to basal ganglia output neurones. Evidence suggests that the fourth decade, and a family history of dystonia is absent.
L-dopainduced dystonia is associated with overactivity of the Injury and over-use may be associated with the onset of dys-
direct striatal efferent pathway to GPm and underactivity of the tonia, although the role of peripheral trauma as a trigger is
projection to GPl. Both of these induce abnormal underactivity unclear. Among musicians, the hand that performs the more

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


complex task is more likely to develop FTSD. Of 129 musi- mal guitarists. Paced, nondystonic tapping of the fifth digit in
cians reported in the literature with FTSD, the right hand was normal pianists causes increased activation of the dorsolateral
affected in 64%. Among keyboard players, 75% involved the precentral gyrus and reduced activation of the supplementary
right hand (n 61), and plectrum instruments had a similar motor area (SMA) and parietal regions compared with non-
predisposition for the right hand (79%, n 19). Among string musicians. Paced, nondystonic tapping in pianists with TSFD
players (violin, viola and cello) the situation is reversed, with was associated with increased activation of SMA and parietal
71% of reported patients (n 24) affected on the left. Al- regions, consistent with a reversion of the activation pattern
though the numbers are small, published examples of flutists typically seen in skilled musicians back to the activation pattern
and clarinetists with FTSD (n 25) support this hypothesis, of non-musicians. These studies identify clear differences in the
with 44% involving the left hand and 54% the right. An in- pattern of brain activation for both dystonic and nondystonic
creasing number of patients with FTSD of the embouchure movements in musicians with TSFD compared with normal
have been recognized. The embouchure refers to the pattern of musician controls.
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- Therapy of Musicians Dystonia
cade, often in one particular register or technique, and were E. Altenmller, H-C. Jabusch, V. Lim
usually insidious and painless. Patients can be categorized into Institute of Music Physiology and Musicians Medicine, Han-
one of four groups by the phenomenology of their movements: nover University for Music and Drama, Hannover, Germany
embouchure tremor, lip-pulling, lip-lock and jaw involvement.
Writers cramp was present in 10% of these patients, and in 5 Musicians dystonia is a task-specific movement disorder
patients (all involving the jaw), dystonia spread to other oral with an unclear etiology. In order to illuminate epidemiology
tasks such as eating or speaking. The diagnosis of FTSD carries and long-term development, follow-up data from 143 patients
profound psychological and financial implications, and therapy diagnosed with musicians dystonia between 1994 and 2000
of FTSD is of little use to a performing artist unless it produces were analyzed. The minimum follow-up period was 6 months.
virtually 100% recovery. To address these needs, the program Questionnaires and standardized telephone interviews were
entity Musicians with Dystonia was founded in January of 2000 used for data collection. Long-term development was recorded
to offer practical support to musicians afflicted with dystonia, by means of self-assessment. Musicians dystonia occurred pre-
to raise awareness of dystonia in the musical community and in dominantly in males (81 %), and mainly in classical musicians
the community at large, and to facilitate research collaborations (93 %). The mean age of onset was 33.4 9.0 years, and in 80
into the cause and treatment of focal dystonia in musicians. % 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
Brain Mapping in Musicians Dystonia
limb prior to the onset of dystonia was found in 9 % of the
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- dystonia were pianists or guitarists and 51 % had professional
ogy Service, VA Boston Healthcare System, Boston, Massachu- positions as soloists. Localization of dystonia was dependent on
setts; 2Department of Neurology, Harvard Medical School, the instrument: 75 % of the diagnosed keyboard instrumental-
Beth Israel Deaconess Medical Center, Boston, Massachusetts, ists had right hand dystonia, in 10 % both hands were affected.
USA 86 % of patients with plucking instruments showed right hand
dystonia. In contrast, string players displayed predominantly
Task-specific focal dystonia (TSFD) in musicians is a dis- left hand dystonia (64 %). In wind players, the disorder oc-
order of skill. The acquisition of skill in musicians may lead to curred as embouchure dystonia in 88 % of brass players and in
adaptive changes in brain function and structure, particularly in
13 % of woodwind players. In woodwind players, the right
those musicians whose training begins at an early age. Neural
hand was affected in 35 %, the left hand in 41 %, both hands
reorganization may result from learning itself, from the repeti-
tive movements involved in practice, or as direct or indirect in 11 %. In general, localization of dystonia was dependent on
consequence of soft tissue and peripheral nerve injuries that work load and complexity of motor tasks. Patients underwent a
may accompany excessive practice. This neural plasticity may variety of treatments such as monotherapies or combination
predispose to the development of TSFD in susceptible musi- therapies with Botox-injections (51 %), Trihexiphenidyl (50
cians. It is unknown what additional factors determine the sus- %), pedagogical retraining therapies (15 %), and ergonomic
ceptibility to develop TSFD; conceivably, genes that govern changes (36 %). In 12 % treatment was not possible or was
brain physiology play a role. Musicians with TSFD show ab- refused. 53 % of all patients reported an improvement in the
normalities in sensory processing and sensorimotor integration. condition, 2 patients (1 %) reported complete alleviation of
There is fusion, distortion, and rearrangement of the cortical symptoms. 35 % showed no change in symptoms, and in 11 %
sensory representation of the digits in musicians with TSFD. In symptoms worsened. Concerning their professional activities,
many instances, neurophysiological abnormalities are observed 31 % of the patients had the same number of performances as
bilaterally in patients with unilateral TSFD. It is unclear wheth- before onset of dystonia and 4 % performed more often. 36 %
er these abnormalities precede or follow the onset of TSFD. had less performances and 29 % changed their profession. An
Dystonic performance in guitarists is associated with reduced objective and comparative evaluation of the different treatment
activation of the premotor area and increased activation of the options requires further studies employing objective measure-
primary sensorimotor cortex compared to performance in nor- ments of therapeutic progress in musicians dystonia.

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


Limb Immobilization for Occupational Dystonia musicians. The age at presentation to the clinic peaked in the
A. Priori, A. Pesenti, S. Barbieri fourth decade of life (45%), and the rest distributed according
Dipartimento di Scienze Neurologiche, IRCCS Ospedale Mag- to age in a bell-shaped curve. Forty-four percent were seen
giore di Milano, Milan, Italy during the first year they became aware of symptoms, while
another 20% were seen 5 years or more after the onset. Among
Because current treatments including botulinum toxin or those with hand dystonias are 34 keyboard players, 15 bowed
drugs often yield disappointing results, focal occupational dys- and 19 plucked string players, 25 woodwinds, and 5 percus-
tonia is a challenging issue in neurological practice, especially sionists. All 13 brass players seen have dystonias affecting the
in certain professional categories such as musicians. Though embouchure muscles as do 3 of the flute players. Among key-
not a life-threatening disorder, it can severely impair a patients boardists 75% had symptoms in their right hands. One of these
social life and destroy a professional career. Interestingly, has evidence of left involvement as well, 2 years after presen-
whereas in patients with focal dystonia the motor area of the tation with the right hand. Among bowed strings 60% have left
cerebral cortex is enlarged and hyperexcitable, in subjects un- hand symptoms, while 95% of plucked strings have right hand
dergoing prolonged a limb immobilization the cortical repre- symptoms. Among the woodwinds with hand dystonias, 64%
sentation of the immobilized muscles shrinks and are hypoex- have left hand symptoms. There are only 5 percussionists, who
citable. We therefore decided to test the effect of limb immo- were divided 3:2 right versus left hand involvement. Patients
bilization in patients with focal dystonia. In a preliminary open were asked about possible precipitants, including trauma,
study in 8 patients we found that after 4 to 5 weeks of limb changes of technique or instrument, and stress. In 67% no cause
immobilization, the benefit of therapy on dystonia varied: in 4 could be clearly identified. Family history of neurological ill-
patients we obtained a good improvement, in 3 a mild improve- ness was mostly negative, although the father of 1 patient had
ment and in 1 no consistent improvement. Hence, we proposed spasmodic torticollis. Included in this report are 1 from each of
immobilization as a possible alternative therapeutic approach to 2 sets of identical male twins, 1 pair being pianists, the other
focal dystonia in selected patients. Despite these extremely violists. All are professionals, trained by the same teachers.
encouraging results, the variability of our patients responses Thusfar only 1 twin of each set is known to be affected with
was large. Unfortunately the sample size was too small for us dystonia. Telephone contact was attempted with all patients not
to try to identify the clinical profile of the best candidate for seen within the past year. Fifty-one were contacted. For 14
immobilization therapy. After our preliminary open study we patients it was 12 or more years since their initial visit. Thirty-
immobilized a considerably larger number of patients, and still three of these were professional musicians, of whom 14 are still
confirmed the variability of the results ranging from marked playing, albeit with changes in technique and/or repertoire. In
improvement, to no improvement at all. With this larger sample none have the symptoms resolved. Seventeen of the profession-
size we tried to find out a posteriori whether patients whose als no longer play. One patient is deceased, 1 has Alzheimers.
dystonia markedly improved had some common features. Our Several who had been primarily performers and others who had
current data suggest that several clinical variables can identify already been primarily teachers, continue teaching. Nine pro
patients who will benefit most from limb immobilization. So fessional musicians changed careers, 2 others retired. A variety of
far the most reliable seem to be a young age (<3537 years); a treatments were used, none of which were felt to be of significant
short disease duration (<1 year from onset of the first symp- help. Only 2 patients had tried Botox. Continued research into
tom); an onset related to overuse; transient improvement after more effective treatments is essential, but of greater priority is
a fatiguing contraction (the hand-grip test); and, possibly, no understanding the etiology(ies) of focal dystonias in musicians so
previous treatment with botulinum toxin. Patients who fulfill all that there can be effective prevention strategies.
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- The Impact of Focal Dystonia on the Working Life of Mu-
mobilization generally fails. sicians Within the United Kingdom
A.G. Butler
Action for Dystonia, Diagnosis, Education and Research,
A Review of 111 Musicians with Focal Dystonia Seen at a Middleton St. George, Co. Durham, United Kingdom
Performing Artists Clinic 1985-2002
A.G. Brandfonbrener and C. Robson Although something is known about the prevalence of dys-
Rehabilitation Institute of Chicago, Northwestern University tonia in general, there was originally little reliable evidence
Medical School, Chicago, Illinois, USA about the incidence of individual types of dystonia within mu-
sicians. However, during the Epidemiological Survey of Dys-
Although among musicians as a whole focal dystonias are tonia (ESD) carried out in Northeast England for over 8 years
uncommon, in a specialized clinic serving musicians focal dys- (since May 1993), a small number of musicians were identified
tonias are seen with greater frequency. We report on a group of with different forms of focal dystonia. The primary author, an
111 musicians diagnosed with dystonia (total instrumentalist ex-professional musician himself, had the opportunity to ad-
patients, 2330) at the Medical Program for Performing Artists dress a conference held in York in England in March 1997,
in Chicago between 1985 and 2002. Excluded were 19 patients which was organised by the British Association of Performing
whose symptoms were compatible with dystonia, but were suf- Arts Medicine. By the time of this conference, the author al-
ficiently atypical to raise questions about the diagnosis. The ready had a good idea of the sense of isolation felt by most
demographics of these patients are similar to those reported by people with dystonia had never been previously measured and
others. Seventy-four percent are men, and 77% are professional as the disorder is predominantly visual in presentation, a num-

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


ber of sufferers felt severe social and psychological pressure to could not be interpreted as psychoreactive. Comparing both
remain hidden from public view. Social isolation in patients patient groups, an overlap was seen in some anxiety subscales
breeds a lack of diagnostic skill in General Practitioners, which as well as in the health concern subscale and somatic com-
in turn leads to non or misdiagnosis and thus increases the plaints subscale of the FPI-R. The findings support the assump-
isolation felt by most sufferers. Therefore the onset of dystonia tion that certain psychological conditions such as perfectionism
for a musician can have a particularly debilitating effect, espe- and anxiety disorders can play a crucial role in the progress of
cially if that musician develops a focal dystonia affecting the musicians disorders such as focal dystonia and chronic pain
hands or the neck. We describe briefly the ESD classification of syndromes. It is possible that these psychological conditions
primary and secondary dystonia and gives the overall preva- may also be triggering factors in the etiology of focal dystonia
lence figures for the various disorders and relates both sets of in musicians. It is necessary to discuss whether the above men-
data to the musicians involved in the study. The 5 case histories tioned psychological patterns and attitudes should be addressed
involve a professional rock guitarist, a semi-professional club in the education of musicians with the particular aim of pre-
guitarist and singer, an amateur classical pianist, a world re- vention of movement disorders.
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 Focal Dystonia in Violin and Viola Instrumentalists
(playing) life of each musician, together with the results and the S.U. Schuele and R.J. Lederman
effectiveness of Botulinum Toxin therapy in the treatment of Department of Neurology and Medical Center for Performing
primary focal dystonia of the hands or neck in musicians. Each Artists, Cleveland Clinic Foundation, Cleveland, Ohio, USA
case history will show how the onset of dystonia has affected
the working life of each musician. Each case history will have Background: Occupational cramp in musicians has been
four sections: 1) the chronological advance of the disorder, 2) recognised for 150 years, but only in the past two decades there
how this affected their playing, 3) any successful treatments, has been a resurgence of interest in this problem. Despite its
and 4) the psychological impact of the disorder on the sub- overall rarity, the diagnosis of focal dystonia is made in a
ject. The impact of focal dystonia makes no distinction be- substantial number of instrumental musicians seeking care for
tween primary and secondary dystonia because an abnormal playing-related problems, ranging from 8 to 14% in two larger
posture or involuntary muscle spasm presents in exactly the series. Methods: We present 22 string instrumentalists (16 vio-
same way in both cases. If the subject becomes unemployed, lin, 6 viola players) seen at the Cleveland Clinic Foundation
due to their dystonia, it does not matter if it was induced, between 1987 and 2001 who were diagnosed with focal dys-
genetically inherited or idiopathicthey are still economically tonia at initial presentation. Of the 22, 17 were professional
vulnerable. 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).
Psychological conditions in musicians with focal dystonia Results: Main complaints were loss of control and/or involun-
and those suffering from chronic pain syndromes tary movements affecting one or several fingers of the finger-
H.C. Jabusch,1 S.V. Mueller,2 V.K. Lim,1,3 E. Altenmueller1 ing hand in 16 patients, the bow arm in 5, and the neck in
Hannover University for Music and Drama, Hannover, Ger- 1 patient. In all patients the symptoms could be confirmed by
many; 2Otto-von-Guericke-University, Magdeburg, Germany; watching them play their instrument. Eleven musicians had an
University of Melbourne, Melbourne, Australia EMG study, and results were abnormal in 4 of them. Two of
these 4 patients underwent surgery for entrapment neuropathy
Focal dystonia in musicians is considered to be a task- without significant or lasting improvement. We conducted a
specific movement disorder which may be of different origins. telephone survey with a standardized questionnaire. Follow-up
Although certain psychological characteristics seem to be pre- information was obtained in 19 out of 22 musicians (mean
dominant in dystonic patients, the role of psychogenesis in the follow-up time, 10.2 years; 14.9 years after onset of symp-
etiology of focal dystonia remains unclear. Psychological con- toms). Treatment attempts included physical therapy, retrain-
ditions were examined in musicians suffering from focal dys- ing, and medication (in most cases trihexyphenidyl). In selected
tonia (n 20) and compared with those of musicians with patients we also offered Botox injections or splint devices.
chronic pain syndromes (n 20) and healthy musicians (n For all these options the response varied between none and
30). Participants were investigated by means of self-estimation mild to moderate improvement. 3 patients reached their previ-
using the revised version of the Freiburg Personality Inventory ous level of performance: 2 by altering their technique and
(FPI-R), a German multidimensional personality inventory, as refingering, the third one, with isolated dystonia of one distal
well as the Questionnaire for Competence and Control Orien- finger, had an excellent recovery after surgical immobilization
tations. An additional questionnaire was developed focusing on of his distal finger joint. Overall, only 6 out of the 19 musicians
perfectionistic tendencies and anxiety disorders. There were were able to stay in their professional careers, the majority
significant differences in the psychological conditions of dys- either became instrument teachers or entirely changed their
tonic musicians compared to healthy musicians. In particular, a professional field. Conclusions: Focal dystonia may affect limb
pattern of anxiety disorders and highly perfectionistic tenden- muscles in violin and viola instrumentalists, often early in their
cies was seen in dystonic individuals. A retrospective inquiry professional career. Currently available therapy offers mild to
revealed that anxiety and perfectionism had already been pre- moderate symptom control; more effective approaches are
sent before onset of focal dystonia, hence these conditions badly needed.

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


Abnormal SensoryMotor Processing of Musicians with flected in the late CNV amplitudes and between movement and
Focal Dystonia. non-movement experiments.
V.K. Lim,1,3 J.L. Bradshaw,2 E. Altenmller3
University of Melbourne, Melbourne, Australia; 2Monash
University, Monash, Australia; 3Institute of Music Physiology Altered Movement Related Cortical Potentials in Musi-
and Musicians Medicine, Hannover University for Music and cians Focal Dystonia when Performing Skilled Movements
Drama, Hannover, Germany with the Affected and Unaffected Hand
Musicians regularly perform complex movements with great T. Peschel,1,2 E. Altenmller1
temporalspatial accuracy and emotion. In some individuals a Hannover University for Music and Drama, Hannover; 2Han-
task-specific, painless cramping or incoordination of the fingers nover Medical University, Hannover, Germany
and hands occurs. This musicians dystonia affects integration Musicians focal dystonia (FD) is characterised by a painless
of the sensorimotor system at multiple levels. Contingent nega- loss of muscular control in highly practiced skilled movements
tive variation (CNV) is an important paradigm for musicians as occurring only in a relevant context. The increased prevalence
it involves a complex interaction between incoming sensory of FD in musicians compared to other occupational cramps
input, motor output and expectations, and is also highly con- may be related to the specific qualities of their sensorimotor
textual. The CNV can be elicited in both movement and non- skills. In addition, the extensive repetitive use of the hand for
movement conditions. Therefore, the CNV and electromyog- years may lead to long term practice-dependent plastic changes
raphy (EMG) were recorded in order to investigate sensorimo- in cortical sensorimotor representations. Movement related cor-
tor integration in musicians with focal dystonia. In this study, 7 tical potentials (MRCPs) reflect the sequential activation of the
male professional pianists presented dystonic flexion symp- sensorimotor cortical areas involved in the planning and ex-
toms primarily in the ring and small fingers whilst playing the ecution of voluntary movements. In this study, MRCPs were
piano. They were compared to control participants who were investigated in a relevant task-specific condition using a grand
matched for age and professional music ability. Tactile stimuli piano. Nine right-handed musicians suffering from FD were
(plastic rods, contact surface of 1 mm) were presented with a compared to an age-matched group of musicians playing the
force of 8.21 1.51 Newtons to the fingernail of the small same instrument and to a group of non-musician controls. MR-
finger. The task employed a simple reaction time paradigm; the CPs were recorded separately for each hand from 11 electrode
participants were given 448 pairs of mechanical warning (S1) locations placed over the sensorimotor cortex. Additionally,
and imperative (S2) stimuli. S1 predicted 75% of the trials EMG of the flexor digitorum superficialis and a trigger signal
where S2 would arrive (valid). The other 25% of the trials, S2 from a prepared Steinway grand piano key were recorded. Sub-
occurred opposite to S1 (invalid). All trials were randomly jects had to play (1) a single note depressing the key with the
presented. Immediately upon presentation of the imperative index finger, and (2) a complex pianistic sequence which in-
stimuli, participants were required to press a button with their duced dystonic symptoms in the patient group and was also
small finger. In addition to the movement experiment, a control playable for non-musicians. All tasks were to be executed on
condition with 224 pairs of trials without movement was con- the grand piano, producing a natural feeling for touch as well as
ducted (presentation of the two experiments were counterbal- sensory and auditory feedback. Musicians compared to non-
anced). The participants were not required to move; however musicians showed higher premovement activity and a reduced
they had to count the number of double stimulations that motor potential especially when performing the complex task.
occurred 25% of the time. Attentional and motivational effects The activation pattern in the patients depended on the perform-
were minimised by subtracting the Non-movement amplitudes ing hand. Compared to musician controls using the non-
from the Movement tasks. This allowed a direct comparison of affected hand, they exhibited reduced premovement and motor
the motor component separate from other aspects of the activity whereas task performance of the dystonic hand was
CNV. There were no significant differences in the amplitudes characterised by higher premovement potentials especially of
of the early CNV (750850 msec). In contrast, for the late CNV the late component 500 to 100 msec prior to movement onset.
(19002000 msec), patients had significantly increased CNV This abnormal activation pattern was also present during a
amplitudes (5.04 mV) compared to controls (1.34 mV). simple key stroke which did not induce dystonic symptoms in
There were no significant differences in the affected and unaf- the patients. The study suggests that repetitive skilled finger
fected hands in either early or late CNV, and no significant movements may lead to functional changes in cortical activa-
EMG differences. Similarly, there was also no significant tion pattern which are most prominent during movement prepa-
group CNV difference between valid and invalid trials (cuing). ration and may reflect use-dependent cortical plasticity in mu-
Central electrodes produced significantly greater amplitudes sicians. Furthermore, our results demonstrate for the first time
than other sites. While the CNV data did not show a cuing that the primary sensorimotor cortex in task-specific focal dys-
effect; reaction time data showed an effect. There was no group tonia, rather then being underactive as indicated by recent
difference in the unaffected hand; however, there was a sig- MRCP studies, may be overactive during movement prepara-
nificant group interaction in the affected hand with cuing. Cu- tion with the affected hand when tested in a task-specific real-
ing had a greater affect on the performance of controls than istic scenario inducing the dystonic movement. The alteration
patients. Valid responses were faster than invalid trials. Con- of MRCPs when using the unaffected hand gives further evi-
trols were also slower than patients in both types of trials (valid dence for a generalized disorder underlying FD. Conclusion:
and invalid). The results suggest that pianists with focal dys- Higher MRCP amplitudes during movement preparation with
tonia have normal arousal and processing of the first stimulus the affected hand reflect either a compensatory mechanism in-
(early CNV). However, the pianists with focal dystonia com- dicating more anticipatory neuronal activity to design the ap-
pared with controls have abnormal inhibition and excitatory propriate movement or reflect defective cortical inhibition due
networks for motor preparation and sensory integration as re- to maladaptive plasticity in musicians dystonia.

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


Cognition and Affect in Patients with Cervical Dystonia vres that involve tactile or proprioceptive stimulation. Although
and Tremor widely recognised, these manoeuvres or gestes antagonistes
K. Vermilion, J. Johnson, D. Duane (GA), have not been systematically analysed. To assess this
Arizona Dystonia Institute/Arizona State University, phenomenon in more detail, we developed and administered a
Scottsdale, Arizona, USA questionnaire to 94 successive patients with idiopathic cervical
dystonia (CD) attending two botulinum toxin clinics (London
Background: Isolating differential characteristics may clarify and Bristol). Sixty patients (63.9%) reported a GA. There were
the relationship between tremor and cervical dystonia. Family no differences between patients with and without a GA in terms
history of movement disorder and psychiatric states, as well as of age (55.2 12.5 years vs. 58.1 10.0 years), sex (women
personal characteristics of cognition, mood and tremor location 63.3% vs. 61.8%), duration of disease (median 13 vs. 11 years),
may differ in patients with (idiopathic) essential tremor (ET) age at onset (median 43 vs. 46 years). Patients with or without
vs. cervical dystonia with tremor (CD/T) versus cervical dys- a GA reported similar levels of control over their head/neck/
tonia without tremor (CDnoT). Objectives: To assess family shoulder position (median 5, on 010 scale). In both groups,
history of movement and mood disorder, and personal qualities torticollis was the most common (91.7% vs. 87.9%), while
of cognition and mood in a referral population of patients with laterocollis (41.7% vs. 45.5%) and anterocollis/retrocollis
CD/T. Methods: 79 CD/T patients (87% women; mean age (25.0% vs. 30.3%) were less frequent. A sizeable proportion of
onset CD, 47 years; mean age onset, T 47 years) were similarly patients in both groups reported head tremor (56.7% vs.
evaluated at mean age 59 years. Analysis included recalled age 66.7%). Among those with a GA, 58.3% of patients discovered
onset CD and T as well as T location; family history of psy- their GA within the year of CD onset, while 35.0% discovered
chiatric and movement disorders; scores on MMPI, Hamilton it later (median 5 years). Additional 6.7% of the patients de-
Depression and/or Spielberger Anxiety Rating Scales; neuro- tected a GA while completing the questionnaire. In the majority
psychological performance on: Rey Auditory Verbal Learning (91.2%) the GA was still effective. The GA target spots were
Test (AVLT), Three Letter Cancellation Task (LCT), Digit mostly located on the cheek (53.3% ) and chin (43.3%), back of
Span (DS), Rey-Osterrieth Complex Figure Test (ROCFT), the neck (45.0%) and head (35.0%). Most patients (86.7%)
Conners Continuous Performance Test (CPT), Test of Vari- reported that the GA effect is dependant on the part of the hand
ables of Attention (TOVA), Wisconsin Card Sorting Test used to touch face/head/neck. The index (59.6%) and middle
(WCST). Results: Family history anxiety 10 (13%) depression (48.1%) fingers and the palm (40.4%) were the most used. The
17 (22%; OCD 5, psychosis 4, alcoholism 29); non-PD tremor 40.0% of the patients described the contact between the hand
38 (48%; head only 13, hands only 17, both head & hands 8), and the face/head/neck as light touch, while 60% described it
dystonia 13 (17%), scoliosis 11 (14%), PD 6 (8%). Personal as push or pull. Touching the GA target spot with an object
evidence anxiety 41 (52%), depression 57 (72%; 7 also OCD). (other than the patients hand) was effective for 26.8%, while
Neuropsychological studies (age adjusted): Impaired AVLT merely thinking of performing the GA was effective for 15.3%.
9/72 (13%), Impaired verbal memory 6 of 72 (8%), Impaired Other people were able to elicit the effect by touching the GA
auditory digital memory 4 of 41 (10%), Impaired visual vigi- target in 27.1% of patients. Most (86.0%) felt that the GA effect
lance (LCT) 46 of 72 (64%), Impaired visuomotor skills 1 of 68 on CD starts either as soon as (42.1%) or shortly after
(1%), Impaired visual memory 11 of 68 (16%), Impaired visual (43.9%) touching the GA target spot, and lasted as long as the
attention (TOVA/CPT) 13 of 14 (93%), Impaired executive spot is touched (87.9%). Interestingly, 7 patients (12.3%) re-
function (WCST) 12 of 21 (57%). Conclusions: As we have ported that the effect on CD starts as soon as hand begins
shown elsewhere, like patients with ET (Vermilion, Stone, Du- moving towards GA target spot. The majority (83.9%) re-
ported that the GA improves their CD by 50%, while almost
ane, 2001), CD/T patients have a high frequency of family
one third (30.4%) felt that the GA improves their CD greatly
history of psychiatric disorder more apt to be depression than
(i.e., >75%) or completely. The GA effect was judged to be
anxiety but both are prevalent as they are in the patients them-
slightly better for improving head/neck/shoulder position than
selves. Similarly, family history of tremor is prevalent in both
for changing neck and shoulder movements and pain. The al-
ET and CD/T, but a greater likelihood that tremor in relatives most ubiquitous presence and remarkable efficacy of the GA in
is of the head in CD/T and of the hands more than head in ET, CD warrants further investigation of its physiology which may
as it is in the affected patients themselves. In patients, psychi- provide clues for understanding the neurobiology of dystonia
atric comorbidity is high in CD/T, especially with respect to de- and open new avenues for its treatment.
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- VI. THERAPEUTICS
tion is also unclear but is similar to that observed in ET.

Clinical Features of the Geste Antagoniste in Cervical Dystonia Dystonia: Medical Therapy and Botulinum Toxin
S.R. Filipovic,2 M. Jahanshahi,1 R.Viswanathan,1 P. Hey- J. Jankovic
wood,3 K.P. Bhatia,1 D. Rogers2,3 Baylor College of Medicine, Houston, Texas, USA
Institute of Neurology, London; 2Burden Neurological Insti-
The symptomatic treatment of dystonia has markedly im-
tute, Bristol; 3Frenchay Hospital, Bristol, United Kingdom
proved, particularly since the introduction of botulinum toxin
A unique feature of dystonia is that patients are often able to (BTX) and as a result of advances in stereotactic surgery. The
reduce/eliminate the abnormal posture using certain manoeu- selection of a particular choice of therapy is largely guided by

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


the severity of the symptoms, data based on clinical trials, nia. Pallidotomy targets the sensorimotor projection from the
etiology of the dystonia, and by personal clinical experience. globus pallidus to the thalamus. A lesion at this site interrupts
Because dopa-responsive dystonia may not be easily differen- the abnormal neuronal signaling in the pallido-thalamo-cortical
tiated from primary dystonia (e.g., DYT1) and is often misdi- pathway that is the putative electrophysiological substrate for
agnosed as cerebral palsy, a therapeutic trial of levodopa should dystonia and other hyperkinetic disorders. The literature on
be considered in all patients with childhood-onset dystonia. pallidotomy for dystonia consists of open-label, retrospective
Unpredictable response and the possibility of undesirable side series that have not used control or comparison groups, confir-
effects, particularly sedation, parkinsonism and tardive dyski- mation of lesion location or long-term follow-up. Despite these
nesia, the use of dopamine receptor blocking drugs in the treat- limitations, numerous recent reports and small series describe
ment of dystonia has been essentially abandoned. Dopamine the outcome of approximately 75 patients in sufficient detail to
depleting drugs, however, such as tetrabenazine, have been make several observations. Bilateral pallidotomy can reduce
found useful in some patients with dystonia, particularly in symptoms of dystonia by 30 to 80%, according to dystonia
those with tardive dystonia. Tetrabenazine has the advantage severity rating scale scores, leading to important improvements
over other antidopaminergic drugs in that it does not cause in gait and function. Bilateral pallidotomy is generally required
tardive dyskinesia, although it may cause transient acute dys- for bilateral or axial symptoms. Primary dystonia seems to
tonic reaction. Anticholinergic medications such as trihexyphe- respond better than secondary dystonia. The reduction in dys-
nidyl have been found to be most useful in the treatment of tonia following pallidotomy is not necessarily acute but can be
generalized and segmental dystonia. This therapy is generally delayed and progressive, suggesting a gradual restoration of
well tolerated when the dose is increased slowly. Some patients normal signaling in the pallido-thalamo-cortical network. But
require up to 60100 mg a day, but may experience dose- despite its advantages over all previous lesion-based ap-
related drowsiness, confusion, memory difficulty, and halluci- proaches for dystonia, pallidotomy seems destined to be re-
nations. Benzodiazepines may provide additional benefit for placed by GPi deep brain stimulation, a technique that in its
patients whose response to anticholinergic drugs is unsatisfac- earliest application appears to be more effective and safer.
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 Pallidal Stimulation for Dystonia
patients with spastic dystonia affecting the legs and trunk. The A.M. Lozano and A. Abosch
introduction of botulinum toxin (BTX) into clinical practice the Division of Neurosurgery, Toronto Western Hospital, Toronto,
late 1980s revolutionized treatment of dystonia. The most po- Ontario, Canada
tent biological toxin, BTX blocks the release of acetylcholine at The net output of the basal ganglia is tightly regulated by the
the neuromuscular junction causing focal chemodenervation activity and balance of driving and inhibitory circuitry. In
and as such it has become a powerful therapeutic tool in the pathological states, disrupted activity in the main outflow
treatment of a variety of neurologic, ophthalmic, and other nucleus, the internal segment of the globus pallidus (GPi) is
disorders manifested by abnormal, excessive, or inappropriate relayed to the motor areas of the thalamus and brainstem. The
muscle contractions. Previously approved for the treatment of behaviour of these targets receiving this disrupted outflow, is
strabismus, blepharospasm and other facial nerve disorders, consequently also disrupted which in turn produces the pro-
including hemifacial spasm, BTX type A (Botox) and BTX found disturbances in motor function that are characteristic of
type B (Myobloc) have been approved by the FDA for the parkinsonian states and certain forms of dystonia. Therapeutic
treatment of cervical dystonia in 2000. The usefulness of BTX efforts are directed at reversing or canceling the pathological
in patients with focal dystonias and other disorders causing basal ganglia output. When drugs are ineffective or have short-
muscle spasms is now well accepted, and BTX has been dem- comings, surgical approaches can be considered. It is interest-
onstrated to have a positive effect on health-related quality of ing and paradoxical that elimination of this abnormal activity
life. Although there is concern about the possibility of immu- with destruction of the motor GPi is usually well tolerated and
noresistance due to blocking antibodies, we have shown that produces little in the way of overt motor deficit. Indeed having
the current Botox, used since 1998, has a relatively low risk of no motor pallidum (as with pallidotomy) appears to be prefer-
blocking antibodies. 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-
Pallidotomy for Dystonia tion. Nevertheless, bilateral pallidal lesions can be associated
B. Ford with significant adverse effects including speech difficulties
Columbia University, New York, New York, USA and cognitive disturbances. It is for this reason that neurosur-
The rationale for treating dystonia using pallidotomy or thal- geons have sought to develop surgical procedures that offer the
amotomy, or indeed deep brain stimulation, is Meyers seminal efficacy of selective pallidal lesions but have a better index of
1942 observation that selectively placed lesions of the basal safety. With the introduction of deep brain stimulation (DBS)
ganglia could abolish abnormal involuntary movements with- to treat first chronic pain and then Parkinsons disease (PD), it
out producing weakness. Many different ablative procedures became logical to apply DBS to treat dystonia. There is now
have been used to treat dystonia over the years. In the last increasing experience in the use of DBS to treat various forms
decade, driven by successful results in treating Parkinsons of dystonia. The initial results suggest that certain primary
disease, advances in neuroimaging, a better understanding of dystonias can show a strong improvement with GPi DBS, and
motor electrophysiology and refinements in neurosurgical tech- the accumulated reports indicate that pallidotomy and pallidal
nique, the modern posteroventral medial pallidotomy emerged stimulation can each be safe and effective treatments for dys-
as the most effective lesion-based treatment for severe dysto- tonia. However, determination of the optimal surgical treatment

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


for dystonia is difficult given the variability in techniques, tar- symptoms following pallidotomy or during pallidal deep brain
gets, underlying pathophysiological mechanisms, the length stimulation. Changes in the pattern of neuronal activity in GPi
and nature of follow-up, the small numbers of patients per could occur as a direct result of transmission of such activity
study, and the lack of blinded, prospective trials. It appears that from the STN, GPe, CM or striatum. They could also occur as
patients with idiopathic generalized dystonia, particularly those the result of increased inhibitory and excitatory activity to the
with DYT1 respond best to pallidal interventions. The response GPi from the striatum and STN, respectively. Such changes in
in secondary dystonias is more variable and reflects the het- excitatory and inhibitory input to the same structure and/or the
erogeneity in the extent of the lesion and distribution of in- presence of strong temporal fluctuations in synaptic inputs have
volvement of neural structures and the accompanying neuro- been proposed to result in the type of irregularity in neuronal
logical deficits. 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-
Dystonia: A Model Based on Electrophysiological Record- portant features for models of dystonia.
ings in the Operating Room.
J.L. Vitek
Emory University, Atlanta, Georgia, USA Off-Period Dystonia in Parkinsons Disease But Not Sec-
Although dystonia has long been considered a hyperkinetic ondary and Primary Generalized Dystonia Is Improved by
movement disorder, the evidence to support such a classifica- High Frequency Stimulation of the Subthalamic Nucleus
tion was based on the presence of excessive involuntary move- O. Detante,1 P. Krack,1 L. Vercueil,1 S. Chabardes,2 A.L.
ment, not on physiological data. Only recently, with the return Benabid,2 P. Pollak1
of surgical procedures using microelectrode guidance for the Neurology Department, Grenoble; 2Neurosurgery Depart-
treatment of dystonia, has electrophysiological data demon- ment, Grenoble, France
strated a decrease in the mean discharge rate of neurons in the Background: High frequency stimulation of the subthalamic
internal segment of the globus pallidus (GPi). In addition to nucleus (HF-STN) improves off-period dystonia in Parkinsons
reductions in mean discharge rates in GPi, examination of disease (PD). As off-period dystonia clinically can mimic gen-
spontaneous neuronal activity in patients with dystonia and eralized dystonia of other causes, we proposed bilateral HF-
hemiballismus have revealed changes in the pattern, degree of STN stimulation to patients suffering from generalized dysto-
synchronization and somatosensory responsiveness of neurons nia. Objective: To compare the efficiency of STN stimulation
in the pallidum. Contrary to the tonic pattern of discharge pres- on off-period dystonia and generalized dystonia. Methods:
ent in normal animals, spontaneous discharge patterns of neu- From a larger series, we selected 22 patients with severe pre-
rons in GPi are highly abnormal in patients with dystonia, operative off-period dystonia rated greater than 3 in at least one
occurring in irregularly grouped discharges with intermittent limb on a severity score ranging from 0 to 4. Four patients with
pauses. Unlike PD, where the mean discharge rate of neurons is generalized dystonia (Hallervorden-Spatz disease, n 3; pri-
increased in GPi and decreased in GPe and the patterns of mary, n1) underwent bilateral HF-STN stimulation. Dystonia
discharge are clearly different, in dystonia the mean rates and of the four limbs was rated in all patients before surgery and 3
patterns of discharge of GPe and GPi neurons appear very months after surgery. Results: In PD, bilateral HF-STN stimu-
similar. The most obvious mechanism to explain the rate lation reduced the severity of off-period dystonia by 70% on the
changes in GPe and GPi is an increase in the inhibitory output 4 limbs (preoperative average severity score 2.03 1.49;
from the striatum via the direct and indirect pathways. Thus, postoperative average severity score 0.6 0,78). Bilateral
one could argue that, at least in primary dystonia, activity in HF-STN stimulation had no effect on generalized dystonia
both the direct and indirect pathways are overactive. Evidence (preoperative average severity score 3.25 0.77 ; postop-
in support of increased activity in the indirect pathway is de- erative average severity score 3.12 0.62). Conclusion: In
rived from the finding of decreased mean discharge rates in spite of clinical resemblance between off-period dystonia in
GPe and increased responses of neurons in GPi to passive Parkinsons disease and generalized dystonia, the effect of
manipulation of the limbs. The increased sensory driving in chronic bilateral HF-STN stimulation was different in these
dystonia, in fact, strongly resembles that which occurs in PD, two pathologies. HF-STN stimulation was highly effective on
where reduced mean discharge rates in GPe leading to in- off-period dystonia in Parkinsons disease, whereas it did not
creased STN drive on GPi is well established, and is consistent improve generalized dystonia. Pathophysiological mechanisms
with studies in primates that suggest proprioceptive input underlying dystonia in these pathologies are still unknown.
reaches GPi largely via the STN. The reduced rate of discharge Assuming that HF-STN stimulation inhibits local neuronal ac-
of GPe would be expected to increase rates in GPi, however, tivity, our findings suggest that they are probably very different
mean discharge rates in GPi in dystonia are not increased. In notably for the STN neuronal activity.
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 Autonomic Side Effects of Botulinum Toxin Type B
activity in the indirect pathway accounts for the observed al- Therapy
teration in receptive field properties of neurons in GPi. While D. Dressler and R. Benecke
increased activity in the direct and indirect pathway can ac- Department of Neurology, Rostock University, Rostock, Ger-
count for the reduction in mean discharge rate and alteration in many
receptive field properties of neurons, changes in the pattern of
neuronal activity in GPi likely plays a key role in the develop- Botulinum toxin type A (BTX-A) has been used for many
ment of dystonia as evidenced by the improvement in dystonic years for treatment of muscle and exocrine gland hyperactivity

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


disorders. Recently, botulinum toxin type B (BTX-B) became dicted by self-esteem and self deprecation, educational level,
available for this purpose. When we started clinical use of employment status, social support, response to botulinum
BTX-B we noticed a side effect profile not seen with BTX-A toxin, disease severity, social participation, stigma, acceptance
before. Altogether 30 patients were included in this study. of illness, anxiety and depression. In multivariate analyses, the
Twenty-four patients suffered from cervical dystonia (CD pa- strongest predictors were anxiety and depression. Severe de-
tients: 9 women, 15 men; mean age, 52.4 13.2 years; duration pression was association with a 19 point decrement on the
of symptomatology, 11.6 8.0 years). Nine of them received physical summary score (95% CI, 31.7 to 6.6; P 0.003),
botulinum toxin for the first time (CD-de novo patients), 15 although disease duration and severity still remained predictors.
were treated with BTX-A until formation of antibodies termi- Conclusions: Care of patients with cervical dystonia must not
nated its efficacy (CD-antibody patients). BTX-B therapy of only focus on reducing the severity of dystonia with physical
cervical dystonia was performed with NeuroBloc (11834.7 techniques. To date psychological aspects have been neglected
2039.3 mU; Elan Pharmaceuticals, Shannon, Ireland). Six pa- and interventions aimed at treating depression and or anxiety,
tients were treated with BTX-B for focal hyperhidrosis (HH especially of a cognitive nature, may have a large impact on
patients: 4 women, 2 men; mean age, 30.7 11.3 years; dura- improving quality of life.
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 Dystonia and Headaches: The Response to Botulinum
the patients was currently on anticholinergic medication. In CD Toxin (BTx) Therapy
patients side effects included dryness of mouth (total, 21/24; N. Galvez-Jimenez, C. Lampuri, R. Patino-Piccirilo, M.
duration, 4.5 1.93 weeks; severe, 10/24; moderate, 7/24; Hargreave
mild, 4/24), accommodation difficulties (7/24), conjunctival ir- The Cleveland Clinic Florida, Weston (Fort Lauderdale),
ritation (5/24), generalised or focal reduction of sweating (4/ Florida, USA
24), heartburn (3/24), swallowing difficulties (3/24), constipa- Headaches, musculoskeletal and other facial pain syndromes
tion (3/24), bladder voiding difficulties (1/24), oral and vaginal are a frequent complaint in patients with cranio-facio-cervical
soor (1/24), dryness of nasal mucosa (1/24) and head instability dystonias. During routine botulinum toxin (BTX) therapy,
(1/24). In HH patients accommodation difficulties (4/6), dry- many patients find these symptoms to be improved. To the best
ness of mouth (2/6), conjunctival irritation (1/6) and swallow- of our knowledge this has not been systematically evaluated.
ing difficulties (1/6) were noticed. Patients without dryness of Our goal was to determine the prevalence, and clinical features
mouth received NeuroBloc 6742.9 3127.8 mU; patients with of the different types of headaches (as defined by the IHS) its
dryness of mouth received 11227.8 2851.9 mU (Mann- relationship with types of cranio-facio-cervical dystonias and
Whitney U test, P < 0.01). Autonomic side effects occur far the response to BTX treatment. The movement disorders data-
more often after BTX-B than after BTX-A and frequently cause base was examined and those patients with cranio-facio-
considerable distress. Their localisation suggests systemic cervical dystonia were identified. Of the 234 patients treated
BTX-B spread. Frequency and nature of motor side effects are with BTX between 1996 and 2001, 70 were included in the
similar to BTX-A. Whether BTX-B has a particularly high study (17 blepharospasm, 8 oromandibular dystonia, 45 cervi-
affinity to autonomic nerve endings and a particularly low af- cal dystonia) with a mean age of 41.85 years (S.D., 14.02).
finity to neuromuscular nerve endings or whether the reverse is Interim analysis demonstrated that most patients (62%) had
true cannot be decided yet. 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
Treatment of the Patient with Cervical Dystonia: Is Botu- concurrent with the onset of dystonia. Migraine type headaches
linum Toxin Enough? (MTH) were noted in 52% of patients and 32% of such patients
T.T. Warner, Y. Ben-Shlomo, L. Camfield related the onset of migraine headaches with the onset of dys-
On behalf of Epidemiological Study of Dystonia in Europe tonia. A great proportion of patients (78%) had a mixed head-
Collaborative Group, London, United Kingdom ache syndrome (CMTTH+MTH). Cervicogenic headache was
Background: Little is known about the quality of life of found exclusively in some patients with cervical dystonia. Fifty
patients with cervical dystonia (CD) and the factors that affect percent of patients with blepharospasm and oromandibular dys-
this. Treatment trials in CD have centred on the use of tonia had CMTTH but no migraine-type headaches. Using a
observer-dependent physical scales and do not incorporate the visual analog rating scale, 67% of patients rated their head-
patients perspective. Objective: To examine how CD affects ache improved from baseline after botulinum toxin treatment.
quality of life. Methods: We studied a cohort of patients from Patients with migraine headaches and those with cervical dys-
seven European countries. Cases completed a postal question- tonia who have CMTTH found relief with BTx when injected
naire which collected data on the SF-36 as the main outcome into the deep cervical paraspinal, trapezius, temporalis and oc-
and a wide variety of explanatory data. Two hundred and eighty cipitalis muscles, in addition to the frontalis, procerus, and
nine subjects (110 men, 188 women; mean age, 55 years) com- corrugator muscles. No ptosis, diplopia, swallowing difficul-
pleted the questionnaire (75% response rate). Results: Cervical ties, or neck weakness was reported. Most patients complained
dystonia had a significant negative impact on quality of life of pain at the site of injection. Some patients had a transient
compared with age-matched general population data. A striking sense of heaviness at the forehead and, at times, transient in-
finding was this negative impact was comparable to other neu- ability to elevate the eyebrows in those treated for blepharo-
rological conditions (Multiple sclerosis, Parkinsons disease spasm or hemifacial spasm when injected at the forehead
and stroke) generally perceived to be of greater clinical sever- muscles (frontalis, corrugator, and procerus muscle). CMTTH,
ity. Both physical and mental quality of life scores were pre- followed by MTH, and other types of headaches and muscu-

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


loskeletal pain syndromes appear to be common concurrent for the UDRS and the BFM may not provide additional infor-
complaints in patients with cranio-facio-cervical dystonias. mation beyond that determined by motor severity scales. Modi-
BTX therapy appears to be effective as migraine and CMTTH fications of these scales may enhance their usefulness.
preventive treatment in dystonic patients.

Analysis of the Duration of Efficacy of Botulinum Toxin

Inter-Rater Agreement for the Ancillary Nonmotor Rating Type B in Patients with Cervical Dystonia
Scales Included in the Unified Dystonia Rating Scale and M.F. Lew
the Burke-Fahn-Marsden Rating Scale for Dystonia. University of Southern California, Los Angeles, California, USA
C.L. Comella, J. Wuu, S. Leurgans, The Dystonia Study Group
Department of Neurological Sciences, Rush Medical Center, Background: Intramuscular injections of botulinum toxin are
Chicago, Illinois, USA widely accepted as treatment of choice for cervical dystonia
(CD). The toxin acts by blocking the release of acetylcholine at
Background: This study was designed by the Dystonia Study the neuromuscular junction, causing a dose-dependent reduc-
Group (DSG) to assess dystonia rating scales used to evaluate tion in muscle activity while producing a reversible paralysis at
dystonia. The Unified Dystonia Rating Scale (UDRS) was de- the site of injection. Because the effects are temporary, repeat
veloped by the Dystonia Study Group and rates dystonia in 14 injection is required periodically to prevent recurrence of
body areas using a motor severity and a Duration of Dystonia symptoms. Botulinum toxin type B (BoNT-B; Myobloc) has
(DOD) factor; the Burke-Fahn-Marsden (BFM) rates dystonia been shown in clinical trials to significantly reduce pain and
in nine body areas using a motor severity and PF factor. Ob- postural abnormalities while improving physical functioning
jective: To assess the inter-rater agreement and internal con- and overall quality of life. Objective: To determine the duration
sistency of the ancillary, non-motor scales of the UDRS and the of efficacy of BoNT-B (Myobloc) injected into patients with
BFM rating scale. Both rating scales have been shown to have CD. Methods: Data on the duration of efficacy of BoNT-B
high inter-rater reliability but are felt to be cumbersome for were compiled and analyzed from two placebo-controlled trials
routine use. Each scale consists of a scale measuring motor and two open-label trials. In the placebo-controlled trials, 186
severity and an ancillary non-motor scale. The ancillary scale in patients received a single injection of BoNT-B at a dose of
the UDRS is the DOD scale. The ancillary scale in the BFM is
5000 U or 10,000 U divided among the affected neck muscles.
a provoking factor (PF) scale. These ancillary scales add com-
Efficacy was assessed by the Toronto Western Spasmodic Tor-
plexity to the rating scale that complicates routine use in a
ticollis Rating Scale (TWSTRS)-Total Scores at Weeks 4, 8,
clinical setting. As a part of a larger study, this study assesses
12, and 16. The first open-label trial included 145 patients and
the usefulness of the ancillary scales by determining the inter-
nal consistency and inter-rater reliability of the ancillary scales. evaluated escalating doses of 10,000 U, 12,500 U, and 15,000
Methods: One hundred patients with dystonia of varying types U. Each patient was initiated on 10,000 U and received the
(focal, segmental, generalized) were videotaped using a stan- subsequent higher dose after returning to their baseline CD
dardized videotape protocol (58 women, 42 men; mean age, 51 status. TWSTRS-Total Scores were assessed every 4 weeks.
years; range, 877 years; mean duration of dystonia, 14 years). The second open-label extension trial included 427 patients.
Ten patient videotape segments were edited onto each of 10 The study was opened to patients who had participated in eight
evaluation tapes. Twenty-five examiners each evaluated 2 previous BoNT-B clinical trials, as well as a small number of
evaluation tapes (20 patients) using the UDRS and BFM, in drug-nave patients. Doses ranged from 2500 U to 25,000 U.
random order. The raters were dystonia specialists not familiar The change in TWSTRS-Total Scores from baseline to Week 4
with the clinical history of the patients. After completing each was used to assess the effectiveness of repeated doses of
scale, the rater completed a questionnaire as to the ease of use BoNT-B. Results: In the two placebo-controlled trials, the
and clinical relevance of each scale. Pooled Kappa statistics mean time to return to baseline CD status was 12 to 16 weeks
were used to assess the inter-rater agreement. Internal consis- in patients treated with BoNT-B. Compared with patients re-
tency of each scale was assessed using Cronbachs . The level ceiving placebo, patients treated with BoNT-B had a signifi-
of statistical significance was set at <0.01. Results: The total cantly longer duration of treatment effect (P < 0.01 in both
scores of the UDRS and BFM showed good agreement among studies). In the first open-label trial, the majority of patients
raters with Intraclass Correlation Coefficients ranging from (<70%) in each dosing phase returned to baseline CD status
0.71 to 0.78. The motor severity section of the UDRS and the between 12 and 16 weeks. There was a trend toward higher doses
BFM had generalized weighted kappas from 0.52 to 0.91. The maintaining a longer duration of effect than the lower dose. With
ancillary scales showed a lower level of agreement, with scores the highest dose of 15,000 U, 1 patient continued to benefit from
for the DOD of the UDRS ranging from .43 to .80 and for the treatment for 48 weeks. In the second open-label extension trial,
PF of the PFM from 0.37 to 0.89. The Cronbachs for the the mean time between treatments varied between 14 and 16
motor severity scores for the original items was equivalent for weeks for treatment sessions 1 through 9. Beginning with the tenth
the severity and the ancillary rating scales, ranging from 0.75 to treatment, there was a noticeable decrease in the mean time period
0.89. Conclusions: This is the first study to evaluate the ancil- between treatments. The shorter mean time between treatments is
lary rating scales for dystonia in a large group of patients likely due to the fact that enrollment for many patients was trun-
among multiple investigators and institutions. This study indi- cated when the sponsor ended the extension trial when BoNT-B
cates that the motor severity ratings show good to excellent was approved by the U.S. FDA and in Europe for the treatment of
inter-rater agreement. Overall, both ancillary scales (the DOD CD. Conclusion: Based on the results of two placebo-controlled
and PF) demonstrate less agreement among investigators and clinical trials and two open-label trials, the duration of efficacy of
increase the complexity of the assessments. The ancillary scales BoNT-B in patients with CD is 12 to 16 weeks.

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