NEUROPSYCHIATRY OF THE BASAL GANGLIA 0193-953>(/97 $0.00 + .

20

DYSTONIA AND DYSKINESIA

Francisco Cardoso, MD, and Joseph Jankovic, MD

Oppenheimln5coined the term dystonia in a report of children who suffered

from a condition characterized by uncontrollable muscular contractions that
produced abnormal postures. Even prior to this description, however, the nine-
teenth century clinicians, including Gowers,4* described patients with similar
movement disorder. With the exception of rare reports, such as the one on the
use of stereotactic thalamotomy for dy~tonia:~ medical literature largely ignored
this condition until 1976. In that year, Eldridge and Fahn3npublished the first
monograph on dystonia. The growing interest in this movement disorder since
then is indicated by the growing number of published studies on dystonia in
recent years. Important milestones in the research of this condition have been
the realization that most cases of dystonia have neurologic and not psychogenic
the identification of genetic markers in some forms of dystonia; the use
of high-dosage anticholinergic and the introduction of botulinum
toxin.13
Dystonia is defined as a syndrome of sustained muscle contractions, fre-
quently causing twisting and repetitive movements, or abnormal postures.’
Although dystonic movements are typically slow and at least transiently sus-
tained, they also may be fast and brief. The characteristic feature of dystonia,
not emphasized in the original definition, is the “patterned” aspect of the
abnormal contractions. This means that the same group of muscles is always
contracting to produce the abnormal posture. The definition implies that dysto-
nia is a symptom rather than a specific disease; and there are many causes of
dystonia, the most common of which is primary or idiopathic dystonia (Table 1).
Despite the large number of studies on dystonia, the second most common
movement disorder seen in movement disorders clinics, this hyperkinesia often
is misdiagnosed. For instance, on average, patients with blepharospasm, focal
dystonia of the eyelids, are evaluated by 10 physicians before being diagnosed
~ o r r e c t l y Although
.~~ the clinical features of dystonia are becoming more fre-

From the Movement Disorders Clinic, Department of Neurology, Federal University of

Minas Gerais, Belo Horizonte, Minas Gerais, Brazil (FC); and the Movement Disorders
Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas (JJ)

THE PSYCHIATRIC CLINICS OF NORTH AMERICA

-
VOLUME 20 NUMBER 4 * DECEMBER 1997 821
822 CARDOSO & JANKOVIC

Table 1. CAUSAL CLASSIFICATION OF DYSTONIA

1. Primary Dystonia Miscellaneous metabolic disorders
Sporadic Wilson’s disease
Inherited Mitochondria1 encephalopathies
1. Classic autosomal dominant Leigh’s disease, Leber’s disease
(Oppenheim’s) dystonia (DYTI gene- Lesch-Nyhan syndrome
9q34) Triosephosphate isomerase deficiency
2. Adult-onset cranial-cervical dystonia Vitamin E deficiency
(DYTG gene-8~21) Biopterin deficiency
3. Adult-onset cervical dystonia (18p) Owing to a known specific cause
II. Secondary Dystonia Perinatal cerebral injury and kernicterus:
Dystonia-plus syndromes athetoid cerebral palsy, delayed onset
Sporadic dystonia
Inherited Infection: viral encephalitis, encephalitis
1. Myoclonic dystonia (18) lethargica, Reye’s syndrome, subacute
2. Dopa-responsive dystonia (DRD, GTP sclerosing panencephalitis, Jakob-
cyclohydrolase I 14q22.1) Creutzfeldt disease, AIDS
3. Rapid-onset dystonia-parkinsonism Other: tuberculosis, syphilis, acute infectious
(RDP) torticollis
4. X-linked dystonia-parkinsonism (Lubag, Paraneoplastic brainstem encephalitis
DYT3 gene-Xql3) Cerebral vascular or ischemic injury
Associated with neurodegenerative disorders Brain tumor
Sporadic Arteriovenous malformation
Parkinson’s disease Head trauma and brain surgery
Progressive supranuclear palsy Peripheral trauma
Multiple system atrophy Toxins: MN, CO, CS2, methanol, disulfiram,
Corticobasal ganglionic degeneration wasp sting
Multiple sclerosis Drugs: levodopa, bromocriptine,
Central pontine myelinolysis antipsychotics, metoclopramide,
Inherited fenfluramine, flecainide, ergot,
Wilson’s disease anticonvulsants, certain calcium channel
Huntington’s disease blockers, ergots
Juvenile parkinsonism-dystonia 111. Other Hyperkinetic Syndromes Associated
Progressive pallidal degeneration with Dystonia
Hallervorden-Spatz disease Tic disorders with dystonic tics
Hypoprebetalipoproteinemia, Paroxysmal dyskinesias
acanthocytosis, retinitis pigmentosa, and Paroxysmal kinesigenic dyskinesia
pallidal degeneration (HARP syndrome) Paroxysmal nonkinesigenic dyskinesia
Joseph’s disease Paroxysmal exertion-induced dyskinesia
Ataxia telangiectasia Paroxysmal hypnogenic dyskinesia
Neuroacanthocytosis Hypnogenic dystonia (probably a seizure
Rett’s syndrome disorder)
lntraneuronal inclusion disease IV. Psychogenic
Infantile bilateral striatal necrosis V. Pseudodystonia
Familial basal ganglia calcifications Atlanto-axial subluxation
Spinocerebellar degeneration Syringomyelia
Olivopontocerebellar atrophy Arnold-Chiari malformation
Hereditary spastic paraplegia with dystonia Trochlear nerve palsy
X-linked dystonia parkinsonism or Lubag Vestibular torticollis
(pericentromeric) Posterior fossa mass
Deletion of 18q Soft tissue neck mass
Associated with metabolic disorders Congenital postural torticollis
Amino acid disorders Congenital Klippel-Feil syndrome
Glutaric acidemia lsaacs syndrome
Methylmalonic acidemia Sandiffer‘s syndrome
Hornocystinuria Satoyoshi syndrome
Hartnup’s disease Stiff-person syndrome
Tyrosinosis Ventral hernia
Lipid disorders
Metachromatic leukodystrophy
Ceroid lipofuscinosis
Dystonic lipidosis “sea blue” histiocytosis)
Gangliosidoses GMI-, GM2-variants
Hexosaminidase A and B deficiency
 DYSTONIA AND DYSKINESIA 823

quently recognized, the disorder still is often wrongly attributed to stress or

other psychological causes. The aim of this article is to provide an overview of
classification, phenomenology, epidemiology, genetics, pathophysiology, neuro-
psychological aspects, and treatment. Emphasis is placed on dystonia associated
with chronic exposure to neuroleptic medications.

CLASSIFICATION AND PHENOMENOLOGY

Classification by Age at Onset

Dystonia can be classified by age at onset as follows: childhood (0-12

years), adolescence (13-20 years), and adult (>20 years).' Abundant evidence
demonstrates that the earlier the onset of dystonia, the greater its tendency
to spread beyond the original anatomic site and to become more 37

Furthermore, early-onset dystonia, particularly common among Ashkhenazi

Jews, often starts in the lower extremities and generalizes following a caudo-
cranial dire~tion.~On the other hand, adult-onset dystonias usually begin in the
upper part of the body, such as the face or the neck, and remain f o ~ a l . ~ ~ , ~ ~

Classification by Cause

Although there are many causes of dystonia, in approximately two thirds

of patients with dystonic movements, no underlying cause is identified (primary
dystonia) (Table 1).@ In contrast to most primary dystonias in which there is no
specific cause, hemidystonias are associated with abnormal imaging studies
indicative of contralateral cerebral hemisphere, usually involving the putamen,
in 75% of patients?', Io9
Subjects with primary dystonia do not display any other findings on neuro-
logic examination besides the dystonic movements. Typically, at the onset,
primary dystonias are present only during the performance of a particular
movement (action dystonia). With progression, a certain action triggers dystonic
movements not only in the area directly involved in the movement but also in
the neighboring regions (overflow phenomenon). In more advanced stages of
the disease, dystonia also becomes evident at rest. If left untreated, dystonia
may progress to a fixed posture and eventual contracture. Another characteristic
feature of dystonia is the phenomenon of sensory trick or geste untugonistique,
which enables patients to temporarily suppress their hyperkinesia by touching
62
the affected area or adjacent body
A history of perinatal hypoxia, encephalitis, exposure to drugs and toxins,
central or peKiphera1 trauma, stroke, dystonia at rest from the onset, sudden
onset, cranial distribution at onset in childhood, or foot involvement in adult-
onset dystonia suggests the diagnosis of secondary d y ~ t o n i a . ~ ~
On, examina-
tion, these patients may have hemidystonia, cognitive deficit, seizures, behav-
ioral changes, ocular/visual disturbances, deafness, dysarthria, focal weakness
or sensory changes, corticospinal signs, reflex abnormalities, fasciculations, and
amyotrophy. Laboratory and imaging investigations are often abnormal. It is
beyond the scope of this article to discuss all causes of secondary dystonias and,
therefore, only the most important ones are highlighted.
Dystonia, usually accompanied by other signs, may be present in several
degenerative diseases. Many patients with Parkinson's disease, especially with
younger onset, develop foot dystonia as the presentating symptom of their
824 CARDOSO & JANKOVIC

parkinsonism."' Although disputed by some, up to 50% of patients with multi-

ple system atrophy have dystonia, particularly anteroco11is.116Blepharospasm
seems to be the most common dystonia in progressive supranuclear palsy,
although cervical and limb involvement also may be present.I5 In the initial
stages of Huntington's disease, the loss of striatal neurons is confined to the
cells that express a-amino-butyric acid (GABA) and enkephalin. This results in
disinhibition of ventrolateral thalamus, with excitation of motor cortex produc-
ing chorea. With progression of the disease, neurons with substance P and
GABA also die, leading dystonia to replace ~ h 0 r e a . lWilson's
~~ disease is an
important disease to diagnose as its early recognition and treatment can lead to
a marked or even complete amelioration of all symptoms. In this autosomal
recessive disease with a mutation in a gene on chromosome 13 and estimated
prevalence of 1:50,000, patients often develop oromandibular and other forms
of dystonia along with tremor, bradykinesia, dysarthria, and other neurologic
abnormalities in the second decade of life.84As Wilson's disease can be treated
effectively, all patients with dystonia beginning in childhood and adolescence
must be screened for it.135It is likely that levodopa and dopamine agonists are
the most common drugs responsible for dystonia. After 5 years on these agents,
at least 50% of patients with Parkinson's disease display levodopa-induced
dyskinesia~.~~ Painless cranial-cervical dystonia usually is associated with high
levels of levodopa (peak-dose dyskinesia), whereas painful lower limb dystonia
is related to low dopamine levels (biphasic and off-period dystonia).l10Dystonia
associated with chronic exposure to neuroleptic agents is described in the section
on tardive dyskinesia.

Classification by Distribution

The clinical features and pharmacologic profile of dystonia varies according

to distribution of parts of the body affected. The ad hoc committee' classified
dystonia based on its anatomic involvement. Focal dystonia is confined to a
single body part, whereas in segmental dystonia there is involvement of adjacent
body areas. Examples of the latter are cranial dystonia manifested by blepharo-
spasm and oromandibular dystonia with cervical dystonia, axial dystonia
(involvement of neck and trunk), brachial dystonia (one arm and axial or both
arms isolated or in association with neck or trunk), and crural dystonia (one leg
and trunk or both legs isolated). In multifocal dystonia, the movement disorder
affects two or more noncontiguous parts. Patients with generalized dystonia
have a combination of crural dystonia and involvement of any other segment.
Hemidystonia involves ipsilateral arm and leg. The clinical features of the most
common focal dystonias are discussed in the following paragraphs.
Cervical dystonia, a condition slightly more common among women, is the
commonest form of focal dystonia seen at a movement disorders clinic. Although
commonly used, the expression spasmodic torticollis is misleading and should
be avoided as these patients usually display a combination of abnormal postures,
not just torticollis (rotation of the neck). Other abnormal postures frequently
involved in cervical dystonia include laterocollis (tilting), anterocollis (flexion),
retrocollis (extension), and a combination of these postures, often associated
with essential or dystonic tremor.19,72 Of the various forms of dystonia, cervical
dystonia most frequently is associated with pain, present in 70% of patients.72
Although spontaneous remission of cervical dystonia may occur in up to 20%
of patients, usually within the first year after onset, most of them develop
recurrence. In the early stages, patients with cervical dystonia often can hold
 DYSTONIA AND DYSKINESIA 825

the head in primary position by using sensory tricks (geste antagonistique), such
as touching the chin, the occipitum, or the cheek.132Blepharospasm, focal dysto-
nia of the eyelids, is the second commonest focal dystonia. Similar to cervical
dystonia, this movement disorder usually starts in the fifth decade of life,
affecting women more often than men. Initially the patients develop excessive
blinking, often wrongly attributed to "dry eyes," which is later followed by more
sustained involuntary closure of the eyelids, resulting in functional blindness in
15% of ~atients.4~ In two thirds of blepharospasm patients, there is associated
dystonia of masticatory, lower facial, pharyngeal, and laryngeal musculature.
Sensory tricks commonly used by patients with blepharospasm include touching
the eyebrow, speaking, and singing.I2Patients with dystonia in the masticatory
musculature, oromandibular dystonia, usually present a pattern of either jaw
opening or closing. Some subjects, however, also have lateral deviation of the
jaw as well as lingual dystonia. As a result of their dystonia, these patients may
experience dysarthria, chewing difficulties, and may become recluse due to
social embarras~rnent.'~ The combination of blepharospasm and oromandibular
dystonia is still sometimes referred to as "Meige's syndrome" after the French
neurologist who studied this condition in 1910?4 Because Meige was not the
first to describe the disorder, the use of this eponym should be discouraged and
the term "cranial dystonia" should be used instead.
In the last century, neurologists described patients who developed difficulty
writing because of abnormal contractions of hand muscles.48For a long time,
these and other occupational cramps were regarded as psychogenic disorders.
Only in the last two decades has a general consensus been reached to classify
writer's cramp as a form of task-specific focal d y s t ~ n i a . " ~There
, ' ~ ~ is a remark-
able interindividual variability in the phenomenology of writer's cramp. In some
patients, the abnormal movement and posture is triggered only by writing
whereas in other subjects any action performed by the arm brings on dystonic
posturing. Besides a tighter grip, subjects with writer's cramp often display
abnormal posturing characterized by a variable combination of flexion, exten-
sion, adduction, abduction, pronation, and supination of the distal arm
In patients with writing tremor it may be difficult to distinguish hand and
forearm muscular contraction intended to compensate for the tremor from true
dystonic contractions. There is an unresolved controversy whether primary
writing tremor is a task specific dystonia or another variant of essential tremor.28
Laryngeal dystonia is much less common than the other forms of focal
dystonia discussed so far. Older terminology includes spastic or spasmodic
dysphonia. The commonest pattern consists of adduction of the vocal cords
leading to a strangled voice with speechless pauses and, not uncommonly,
shortness of breath (adductor laryngeal dystonia). A few patients produce a
whispering voice as a result of abduction of the vocal cords (abductor laryngeal
dystonia)? Similarly to writer's cramp, only in recent years has evidence sup-
porting an "organic" cause of laryngeal dystonia been pre~ented.~~, 86

Generalized dystonia accounts for about 10% of patients with dystonia seen
at specialized centers.3zMost of these patients have primary (idiopathic) dysto-
nia. The onset is typically at 6 to 10 years of age, often starting in one of the
legs, but the disorder becomes generalized usually before adolescence. Initially,
childhood-onset primary dystonia often presents as action distal dystonia, mani-
fested, for example, by foot inversion when walking or running or by writer's
cramp. Later, the symptoms become evident even at rest, and may evolve into
fixed contractures?o Axial (trunk) dystonia may present as or progress into
scoliosis or kyphosis. Although only a few patients with generalized dystonia
are wheelchair-bound or bedridden, virtually all of them display gait impair-
826 CARDOSO & JANKOVIC

ment. Pain is a salient feature chiefly in patients with cervical i n v o l ~ e m e n t . ~ ~

Primary dystonia should be differentiated from dopa-responsive dystonia
(DRD), another autosomal dominant, childhood-onset, generalized dystonia.
Some have estimated that up to 10% of patients with childhood-onset dystonia
have DRD.lZZThe presence of diurnal fluctuation, that is, dystonia worsens as
the day progresses, an exacerbation after physical exertion, and parkinsonian
features (rigidity, bradykinesia and, less often, rest tremor) suggest the diagnosis
of DRD, although up to 10% of patients are clinically indistinguishable from
those with primary dystonia.Iu2, Iu3

GENETICS

A genetic linkage studies of a large non-Jewish family found that autosomal

dominant dystonia is linked to a gene marker on chromosome 9q32-34, named
DYT1.'06 Although EldridgeZ9suggested that this condition was inherited as an
autosomal recessive trait among Jews, more recently Kramer and c011eagues~~
demonstrated that the DYTl dystonia is also responsible for the typical child-
hood-onset dystonias in this ethnic group and that it is inherited in an autosomal
dominant pattern. There is, however, a higher penetrance among non-Jewish
families (0.50-0.75) than in Jews (0.30-0.40).76
DRD is inherited in an autosomal dominant manner with a penetrance of
15% in men and 45% in women.1u2Recent evidence shows that its gene is
mapped to chromosome 14q.Iu4Ichinose and colleagues55showed that this locus
on chromosome 14 is associated with mutations in the GTP cyclohydrolase I
gene. This defect prevents the synthesis of tetrahydrobiopterin, an essential
cofactor for tyrosine hydroxylase, leading to dopamine deficiency. In families
where there is DRD with marked diurnal fluctuation there is also linkage to the
same gene on chromosome 14q.IZ9
Lubag is a recessive X-linked form of dystonia confined to men from the
Panay Island, Phillippines, or their descendants. The onset is in the late 30s, and
the patients display a combination of dystonia and parkinsonism.81,82 The gene
responsible for X-linked dystonia-parkinsonism syndrome, DYT3, is linked to
markers on chromosome Xq13.79 There still remains a possibility, although
disputed, of autosomal recessive generalized dystonias among Spanish Gyp-
~ies.~~
The genetics of adult-onset dystonias is less clearly understood. A popula-
tion-based study performed in the United Kingdom by Waddy et allx suggests
that DYTl accounts for most forms of idiopathic focal dystonias. The concept
that genetic factors play a role in the origin of idiopathic focal dystonias is
supported by the finding that 23% of patients with these movement disorders
have affected relatives.128The gene responsible for idiopathic focal dystonias,
however, remains to be determined.
Bressman and colleaguess performed linkage analysis for the 9q34 region
on a large family with non-DRD. There were seven affected family members,
five of whom had the dystonia restricted to the upper half of the body, and two
patients had generalized dystonia. The authors were unable to demonstrate
linkage to DYTl. Holmgren and colleagues52recently have demonstrated that
autosomal dominant adult-onset idiopathic torsion dystonia in a Swedish family
is not related to DYTl. Taken together, these findings suggest that there is
genetic heterogeneity among inherited forms of dystonia. It is also likely that
many sporadic cases of dystonia represent phenocopies. Since the original link-
age study by Ozelius and other gene loci have been identified for
 DYSTONIA AND DYSKINESIA 827

phenotypically similar or different primary dystonias on chromosomes 8 and

18; and it is very likely that new dystonia-related gene loci and gene mutations
will be discovered in the future (Table 1).

EPIDEMIOLOGY

There are few available studies on epidemiology of primary dystonias. In a

study in Rochester, MN, Nutt and colleagueslOZfound the prevalence and inci-
dence of generalized idiopathic torsion dystonia to be, respectively, 3.4 per
100,000 of the population and 2 per million person-years. This prevalence con-
trasts with the value of 6.8 per 100,000 among Ashkhenazi Jews living in 1 ~ r a e l . I ~ ~
The X-linked dystonia-parkinsonism syndrome, a disease confined to Visayans
on the island of Panay, Philippines, affects 1 in 4000 men living in that area.8I
Focal dystonias are 10 times as common as generalized forms. In the
Rochester, MN study,1o1for instance, the prevalence of focal dystonias was
estimated to be 30 per 100,000 of the population. These same authors'O' found
incidence (per million person-years) of cervical dystonias, blepharospasm, oro-
mandibular dystonia, spasmodic dysphonia, and writer's cramp to be, respec-
tively, 10.9, 4.6, 3.3, 2.7, and 2.7. Regarding cervical dystonias, this corresponds
to a prevalence of 8.9 per 100,000. In a more recent study in this area also
assessing the population referred to the Mayo Clinic in Rochester, Claypool et
alZ1found the prevalence of cervical dystonia to be 1.2 per 100,000. The authors
recognize, however, that these values underestimate the real prevalence and
incidence because their study was performed on a hospital-based population.
One may argue that patients with milder disease did not seek medical attention
and were not included in the study. This conclusion is supported by the finding
that the prevalence of writer's cramp among office workers is 5.4 per 100,000.'20
In a community-based study in Japan, the prevalence of focal dystonias was
found to be 6.2 per 100,000, suggesting that, similarly to idiopathic generalized
dystonias, the frequency of focal forms may vary among different ethnic

PATHOLOGYANDPATHOPHYSIOLOGY

No consistent abnormalities have been found in the few brains of patients with
idiopathic dystonia, whether hereditary or sporadic, generalized or focal.40,u, 71, 139
Hornykiewicz et a153and Jankovic et a171 performed biochemical studies and
found decreased norepinephrine levels in the lateral and posterior hypothala-
mus, mammillary bodies, subthalamic nucleus, and locus coeruleus. On the
other hand, there was increased norepinephrine levels in the septum, thalamus,
colliculi, red nucleus, and dorsal raphe nucleus. Serotonin levels were increased
in the pallidum, subthalamic nucleus, and locus coeruleus but decreased in the
dorsal raphe nucleus. Dopamine levels were reduced in the nucleus accumbens
and the striatum. Hornykiewicz et a153suggested that the decreased levels of
norepinephrine lead to increased cholinergic activity. In autopsies of patients
with atypical findings, Gibb et a145found a mosaic pattern of gliosis in the
striatum. Other studies have disclosed pontine angioma, gliosis in brain stem
nuclei, and Lewy bodies.46* 78 As these authors did not study normal or diseased
controls, one may argue that these findings are most likely coincidental.
In patients with focal or generalized idiopathic dystonias, imaging investiga-
tions fail to find any abnormality. On the other hand, several studies of patients
828 CARDOSO & JANKOVIC

with secondary dystonias have identified lesions in the contralateral basal gan-
glia, cerebral cortex, and thalam~s.9~ Marsden et a1,9I for instance, reported on 28
patients with hemidystonia with lesions in the contralateral striatum, pallidum,
thalamus, or variable combinations of these structures. Lesions of other struc-
tures, however, may be related to dystonia. Jankovic and Pate1,66 for example,
reported on the association between blepharospasm and rostra1 brain stem
lesions. More recently, there are reports of a cerebellar lesion associated with
ipsilateral dystonia as well as on upper cervical spinal cord tumor and cervical
dystonia.". 119 It should be mentioned, however, that despite the frequent occur-
rence of lesions in the basal ganglia in patients with dystonia, lesions in these
structures usually are not followed by d y ~ t o n i a .82,
~ 93
~,
Electrophysiologic studies performed on patients with dystonia consistently
have shown hyperexcitability of interneurons involved in the generation of
motor phenomena.118Several author^^^,^^^ have found lack of reciprocal inhibition
between agonists and antagonists in the affected forearm of patients with
writer's cramp. Panizza et alloa also demonstrated the existence of a similar
phenomenon in patients with generalized dystonia, blepharospasm, and cervical
dystonia. More recently, Chen et alZ0were able to reproduce these results in
writer's cramp patients, and they also showed that there is a similar lack of
inhibition in the contralateral, nonaffected arm. These authors hypothesize that
this contralateral abnormality accounts for the development of writer's cramp
in many patients who shift hands for writing. Taken together, these findings
suggest that focal dystonias may represent a localized expression of a wide-
spread neurophysiologic abnormality. It is speculated that this lack of inhibition
underlies the co-contraction of agonists and antagonists, a classic electrophysio-
logic feature of dystonia.l18
Hyperexcitability of interneurons also has been demonstrated at supraspinal
levels. Berardelli et a1,3 for example, showed that the recovery of the blink reflex
in patients with blepharospasm and oromandibular dystonia is quicker than in
controls. Tolosa et found similar changes in patients with cervical dystonia.
More recently, Aramideh et a12 confirmed the existence of abnormalities in the
recovery of the blink reflex in patients with blepharospasm. Their finding that
distinct muscles are involved by dystonia in different patients suggests, how-
ever, that several mechanisms may underlie the eyelid closure.
The exact role of brain stem and spinal interneurons in the generation of
dystonia remains to be determined. Hyperexcitability of these structures in
patients with primary dystonia suggests that these areas either are disinhibited
or activated by altered outflow from the basal ganglia.118Indeed, Mitchell et al,97
studying dystonia induced by dopamine agonists in nonhuman primates with
MPTP-induced parkinsonism, demonstrated increased activity in the putamino-
pallidal and pallidosubthalamic pathways and decreased activity in the subthala-
mopallidal and pallidothalamic pathways. These changes likely lead to motor
cortex abnormalities. This hypothesis is supported by studies in humans show-
ing enhancement of the N30 potential, probably generated in the supplementary
motor area,113and low-intensity transcranial magnetic stimulation inducing
higher amplitude motor-evoked potentials in dystonic patients than in controls.9z
Furthermore, Van der Kamp et found reduced peak-amplitude of move-
ment-related electroencephalogram potentials in patients with arm dystonia;
and in another study of task-specific dystonia, Ridding et aln5 demonstrated
decrease in cortico-cortical suppression. Although most authors believe that
these cortical abnormalities are secondary to basal ganglia dysfunction, after
studying focal dystonia patients with positron emission tomography (PET),
Tempe1 and P e r l m ~ t t e r raised
* ~ ~ the possibility that they might reflect primary
 DYSTONIA AND DYSKINESIA 829

dysfunction of cortical inhibitory interneurons. More recent PET data, however,

confirm the existence of metabolic dysfunction of the cortex as well as of the
basal ganglia.17,I f l , 27 More specifically, these and other studies provide evidence
for overactivity of the anterior supplementary motor area (SMA) (planning) and
dorsal prefrontal area and underactivity of the caudal SMA (executive) and
motor cortex. In addition, there is evidence that in dystonia, in contrast to
Parkinson’s disease, the indirect, D2 dopamine receptor mediated pathway is
underactive, whereas the direct, D1 dopamine receptor mediated pathway is
overactive. Future physiologic and metabolic studies should provide additional
insights into possible explanations as to how these abnormalities result in dys-
tonic movements.

NEUROPSYCHOLOGY

Until the 1970s, dystonia was regarded as a psychogenic neurologic disor-

der.88 Since then, an impressive body of evidence, reviewed by Jankovic and
Fahn,62 supports an organic basis for dystonia. One strong argument in favor
of this theory is the finding that brain lesions may cause dystonia clinically
indistinguishable from idiopathic forms.66, 82, 91, Io9
Few formal neuropsychological studies have been performed on dystonia
patients. Sheehy and Marsdenlz3demonstrated that the prevalence of psychologi-
cal problems in patients with writer’s cramps and controls is not statistically
different. Similarly, comparing patients with cervical dystonia with patients with
cervical spondylosis, Jahanshahi and M a r ~ d e nfailed ~ ~ to find differences in the
prevalence of psychiatric disorders between the two groups. These results were
reproduced by Duane and Berman.26Jahanshahi and M a r ~ d e nshowed, ~~ how-
ever, that depression of cervical dystonia patients differed from that in the
control group in terms of fewer biologic symptoms but a greater frequency of
negative self-related conditions, such as self-blame, self-accusation, self-punitive
thoughts, and negative body-image. In another study, the same con-
firmed those conclusions, finding a direct relationship between perceived dis-
figurement and depression in cervical dystonia. One possible consequence of
these findings is that pharmacotherapy may be insufficient to relieve depression
in dystonia.f18Interestingly, treatment with botulinum toxin (BoTx) significantly
decreased d e p r e ~ s i o nTaken
. ~ ~ together, these studies indicate that psychological
factors do not play a significant role in the genesis of dystonia. They also suggest
that, like any chronic diseases, dystonia produces psychological impact, often
expressed as depression.
Paradoxically, after great efforts to establish an organic basis for dystonia,
it became clear that up to 3% of all dystonias are Fahn and
Williams36defined four categories of psychogenic movement disorder. In order
for the psychogenic movement disorder to be categorized as ”documented,” the
symptoms must be relieved completely by psychotherapy, by the clinician utiliz-
ing psychological suggestion, or by the administration of placebos. Also, the
patient must be witnessed as being free of symptoms when left alone supposedly
unobserved. Patients with ”clinically established” psychogenic movement disor-
der have a condition inconsistent over time or incongruous with a classical
movement disorder and have additional manifestations suggesting a psy-
chogenic origin. The latter include definite psychogenic neurologic signs, multi-
ple somatizations, an obvious psychiatric disturbance, the disappearance of the
movement disorder with distraction, and excessive slowness of movement. The
other two categories are probable and possible psychogenic movement disorder.
830 CARDOSO & JANKOVIC

Based on these criteria, Fahn and Williams36described 22 patients (20 women)

who met the criteria for the first two categories. They also listed features
suggestive of psychogenic dystonia: abrupt onset, inconsistent movements, in-
congruous movements and postures, rhythmic shaking, bizarre gait, deliberate
slowness in carrying out the requested voluntary movement, bursts of verbal
gibberish, excessive startle, entrainment of the psychogenic tremor to the rate of
the requested rapid successive movement that the patient is asked to perform,
demonstration of exhaustion and fatigue, spontaneous remission, disappearance
of movements with distraction, response to placebo or suggestion or psychother-
apy, and dystonia beginning as a fixed posture. Finally, as there is no biologic
marker for dystonia, it must be emphasized that the diagnosis of psychogenic
dystonia is very difficult and should be made only by clinicians skilled in the
diagnosis of movement disorders.

TREATMENT

Generalized Dystonia

Patients with generalized dystonia, particularly those with onset in child-

hood or adolescence, should be treated initially with levodopa because up to
10% of these patients have DRD.Io2The authors usually initiate therapy with
levodopa/carbidopa at a dose of 100/25 mg one-half tablet twice a day to be
gradually increased up to 250/25 three times per day, although this high dosage
is only rarely needed. If no improvement is noticed by the end of 2 months, we
discontinue this drug and introduce therapy with anticholinergic agents. Al-
though trihexyphenidyl has been studied most extensively, it is likely that other
anticholinergic medications or antihistamines, such as biperiden and dipheny-
dramine, are also effective. O ~ e n - l a b e and
l ~ ~ do~ble-blind~
studies demonstrated
that up to 70% of patients with generalized dystonia improve substantially on
high-dosage anticholinergic agents. The required daily dose of trihexyphenidyl
is 30 to 40 mg, but doses as high as 100 mg daily may be necessary. Unfortu-
nately, only half of the patients maintain the same response in the second year
of treatment. The drug should be increased gradually to improve tolerability.
The patients should stay on a certain level of the drug for 3 weeks as it may
take this period of time for improvement to be noticed. Young age, short
duration of dystonia, and milder movement disorder predict a better response
to anticholinergic medications. Peripheral side effects include blurred vision,
dryness of the mouth, and urinary retention. Central side effects, more common
in adults, are confusion, memory loss, disorientation, and hallucinations. If the
response to high-dosage anticholinergic medications is unsatisfactory or the
patient is unable to tolerate the drug, the next step is to add baclofen. Dosages
as high as 100 mg a day of this GABA-B receptor agonist may be needed to
observe beneficial effectsmContinuous intrathecal infusion of baclofen has been
found helpful in some patients, particularly those with secondary forms of
dystonia, who failed to improve with oral b a ~ l o f e n .loo ~ ~Dopamine
, depletors,
such as tetrabenazine or reserpine, help some patients who fail to improve with
anticholinergic agents and baclofen.61Less useful options are benzodiazepines
and carbamazepine. Although neuroleptic drugs should be avoided because of
the potential to cause tardive dystonia, the combination of pimozide, tetrabena-
zine, and trihexyphenidyl can be used in patients who remain disabled despite
the use of all previously mentioned drugs.
Besides pharmacologic therapy, patients with generalized dystonia may
 DYSTONIA AND DYSKINESIA 831

require BoTx injections to treat focal problem~'~and stereotactic thalamotomy.16

In a recent study, Cardoso et all6 showed that about 50% of carefully selected
patients, whose dystonia continued to produce disability despite optimum phar-
macologic therapy, may benefit from thalamotomy. Because pallidotomy clearly
helps patients with Parkinson's disease with levodopa-induced dyskinesia, in-
cluding dystonia, this surgical intervention currently is being investigated in
several centers. These treatment guidelines are also applicable to hemidystonia,
which thalamotomy is particularly useful for, and multifocal dystonia.

Focal Dystonias

Chemodenervation with BoTx is considered to be the first choice treatment

for most focal dy~t0nias.I~ Although there are seven serologic types of BoTx,
only types A and, to a lesser extent, B, C, and F have been investigated clinically.
Only BoTx type A is currently available commercially, and, therefore, the present
discussion focuses on this serotype. BoTx prevents the fusion of acetylcholine-
containing vesicles with the presynaptic membrane of the neuromuscular
junction, leading to denervation of the injected muscle. In the last few years, the
molecular mechanism of action of BoTx has been elucidated.I2lThe heavy chain
of the toxin, whose molecular weight is 150 kDa, promotes its binding to the
axon membrane and subsequent internali~ation,'~~ whereas the light chain is a
zinc-dependent p r o t e i n a ~ eThe
. ~ ~ target of the enzyme are proteins involved in
the docking of the synaptic vesicle to the membrane. BoTx type A, for instance,
cleaves soluble NSF attachment protein of molecular weight 25,000 (SNAP-25).'
After the toxin injection, the terminal portion of the axon degenerates irrevers-
ibly but sprouting starts in 7 days, re-establishing the muscle innervation after
a variable period of time, usually 3 to 4 months.124The implication of this
finding is that the benefits and complications of BoTx injections are transient.
The development of antibodies against the toxin is one potential problem of the
BoTx use. High doses of toxin per treatment session, treatment frequency greater
than one injection every 3 months, and "booster" injections (i.e., another
injection within 2 to 4 weeks following the first injection) have been identified
as risk factors for the development of antibodies.68Patients who develop immu-
noresistance to type A BoTx may respond well to other serotypes, such as B and F.
Marked to moderate improvement lasting a mean of 14 weeks is seen in
approximately 90% of patients with blepharospasm. The most common side
effects include pain at the site of the injection, ptosis, diplopia, and increased
tearing.31, BoTx injections benefit 80% to 90% of patients with cervical dystonia
for a mean of 12 weeks. The most common possible complications, which may
occur in up to 40% of patients, are pain at the site of injection, swallowing
difficulties, neck weakness, and enhanced head tremor.67,83 More than 90% of
patients with adductor laryngeal dystonia who undergo BoTx injections in the
vocal cord muscle experience meaningful improvement lasting 16 to 20 weeks.
Less than one quarter of the patients develop complications, such as pain at the
injection site, hoarseness, and transient d y ~ p h a g i aThe
. ~ ~ treatment of abductor
spasmodic dysphonia is usually more challenging, although up to 75% of pa-
tients experience an 80% impr~vement.~ BoTx provides moderate to marked
improvement in 58% to 84% of patients with writer's cramp, regardless of the
use of electromyography guidance, although most of them develop transient
hand or finger weakness.z2,69, 112, 136 Oromandibular dystonia is one of the most
difficult forms of dystonia to treat with BoTx, but most patients with this form
of dystonia rarely respond to any other treatment. Approximately 70% of pa-
832 CARDOSO & JANKOVIC

tients with jaw-closing dystonia experience improvement in chewing and speech

with injection of BoTx into the masseter muscles, but only 50% of subjects
with jaw-opening type experience similar improvement when injected into the
submental muscle complex or the lateral pterygoid m~sc1es.l~ Despite the limita-
tions of BoTx use for oromandibular dystonia and writer’s cramp, it is the only
effective available therapy for these conditions.
If, for any reason, patients with focal dystonias do not have access to BoTx,
pharmacologic treatment may be tried (Table 2). The efficacy of these drugs,
however, is limited, and the patients often experience undesirable side effects.
Thalamotomy should not be considered for focal dystonias.16Surgical peripheral
denervation may be recommended for cervical dystonia patients who fail to
improve with other therapies.

TARDIVE DYSKINESIA

The term turdive dyskinesiu (TD) encompasses a broad spectrum of hyper-

kinesias associated with exposure to neuroleptic drugs within 6 months of the
onset of symptoms and which persist for at least 1 month after the discontinua-
tion of the offending agent.=,95, l Z 5 Although prevalence figures range from 0.5%
to 65%, TD studies suggest that approximately 30% of patients exposed to
dopamine receptor-blocking drugs develop some persistent movement disor-
der.44,73,74
Differences in the definition of TD as well as in the studied populations
may explain the discrepancy in prevalence figures among different studies. For
instance, hospital-based studies are more likely to find higher prevalence of
TD than community-based Prospective studies have shown annual
incidence to range from 3.7% to 12%.56,75 Defined risk factors for development
of TD are affective disorder, female gender, age, total cumulative drug exposure,
and persistence of neuroleptic use after development of TD.41,73, 75
The underlying mechanism of TD remains to be determined.60The dopa-
mine receptor blocking action of the offending agents as well as the transient
improvement of TD with use of higher doses of neuroleptic medications support
the notion of upregulation of dopamine receptors in the basal ganglia.’O Evidence
directly supporting this hypothesis, however, is still lacking.24Alternative, yet
unproved, hypotheses include imbalance between D1 and D2 subpopulation
changes in GABA systern5l; hyperactivity of the direct pathway
connecting striatum with pars reticulata of the substantia nigra and inner seg-
ment of the globus pallidum, leading to disinhibition of the ventrolateral thala-
mu^^^; and free radicals g e n e r a t i ~ n . ~ ~
From a phenomenologic standpoint, the hallmark of TD is the co-existence

Table 2. PHARMACOLOGIC TREATMENT OF FOCAL DYSTONIAS

Cervical dystonia Orornandibular dystonia
Anticholinergics Baclofen
Baclofen Doparnine depletor + lithium
Doparnine depletors (tetrabenazine Anticholinegics
or reserpine) Laryngeal dystonia
Benzodiazepines Anticholinergics
Blepharospasrn Writer’s cramp
Clonazepan Anticholinergics
Anticholinergics Baclofen
 DYSTONIA AND DYSKINESIA 833

of different movement disorders. In a study of 100 consecutive patients with

TD, Stacy et demonstrated that 70% of patients displayed a combination of
several hyperkinesias. Stereotypes (repetitive purposeless but seemingly pur-
poseful movements) and dystonia were the commonest movement disorder
displayed by the studied patients. The most frequent stereotypies observed in
the studied population involved the cranial region with masticatory movements
and protrusion of the lips and tongue. Indeed, these stereotypies are so common
that many authors and physicians simply label them TD. Tardive dystonia,
typically seen in young adults, is characterized by prominent axial involvement
and opisthotonic posturing, often associated with repetitive arm extension and
pronotion. Rest tremor related to drug-induced parkinsonism is not regarded as
TD; however, tardive tremor, present as rest and action tremor, may be the only
manifestation of TD.Iz6Other movement disorders often present in patients with
TD are akathisia, tics, myoclonus, tremor, and chorea.
The most important treatment of TD is the discontinuation of the offending
agent. After an initial increase in the movement disorder severity, most patients
will experience improvement of TD. The frequency of complete remission varies
depending on the age, gender, and cumulative dose of the offending drug. On
average, about 30% of patients reach remission.” Many patients, particularly
those with psychiatric conditions, are unable to remain off neuroleptic medica-
tions. Under these circumstances, the only drug not associated with the develop-
ment of TD is clozapine, an atypical neuroleptic agent with high-affinity for D4
receptors.85Dopamine-depleting agents, such as tetrabenazine and reserpine, are
the most useful agents to treat the movement disorders associated with TD.39 ffi
Although equally effective, tetrabenazine is much better tolerated than reserpine.
Patients with dystonia as the most important dyskinesia may benefit from the
same strategies previously mentioned in the section on treatment of dystonia.
The management of tardive akathisia may be particularly challenging despite
the use of dopamine-depleting agents, propranolol, opioid agents, and atypical
neuroleptic agents.

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Francisco Cardoso, MD
Department of Neurology-UFMG
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