Overview of Dystonia
Dystonia is a neurologic movement disorder characterized by sustained
muscle contractions, usually producing twisting and repetitive movements
or abnormal postures or positions. Almost all dystonic movements share
a directional quality that is typically sustained, sometimes for an
instant, as well as a consistency and predictability Dystonia movements
are directional, forcing the involved body part or region into an abnormal
position, which is consistently present.
Classification of Dystonia
Dystonia is classified in a number of ways including...
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Age at which symptoms appear. Symptoms may become apparent during
childhood, adolescence, or adulthood.
Area or areas of the body that are affected. Sustained muscle
contractions and abnormal movement patterns may be limited to one
area of the body; involve two or more areas of the body that are
next to each other, as in segmental dystonia or two or more areas
of the body that are not next to each other (non-segmental or
multi-focal); or be generalized in nature, including leg
involvement and other areas of the body.
Cause. Dystonia may occur as a primary condition (idiopathic
dystonia) that is familial or occurs in the absence of a family
history. It may result from certain environmental factors or
"insults" that affect the brain (secondary or symptomatic dystonia).
Dystonia may be associated with certain nondegenerative,
neurochemical disorders (known as "dystonia-plus syndromes") that
are characterized by neurologic features, such as parkinsonism or
myoclonus. Dystonia is also a primary feature of certain, usually
hereditary, neurodegenerative disorders (so-called
"heredodegenerative dystonias").
Dystonia and its Relationship to Activity
Dystonic movements or posturing are often described as they relate to
activity or factors that may aggravate symptoms.
Dystonia, particularly primary dystonia, of a body part may...
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Occur only during voluntary movement or become worse during these
movements. This is known as action dystonia. Dystonia that appears
only with specific actions, such as writing (i.e., "writer's
cramp"), is a task-specific dystonia. Primary dystonias often begin
as task-specific yet eventually appear with other activities as the
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condition progresses. For example, dystonic cramping and spasms
that initially appear only when writing may eventually occur during
other activities, such as eating.
Occur with voluntary movements of other, unaffected bodily regions.
This phenomenon, known as "overflow," may develop as a dystonic
condition progresses.
Occur even when the affected body part is at rest. This is referred
to as rest dystonia. Rest dystonia may develop with further
progression of a dystonic condition and therefore is typically
considered more severe than action dystonia.
Lead to sustained, abnormal, fixed postures or positions of
affected body regions, potentially causing permanent contractures.
Dystonic contractions are relatively slow or rapid in speed, sometimes
resembling other neurologic movement disorders, such as the "shock-like"
muscle contractions seen in myoclonus or the irregular, relatively brief
movements of chorea. Dystonic movements are more closely associated with
prolonged bursts of electrical activity in affected muscle(s) rather than
the short, irregular bursts of myoclonus. In addition, dystonic movements
tend to have a sustained, directional nature rather than the random,
flowing contractions seen with chorea. Dystonia also typically may be
distinguished from the involuntary, rhythmic, "back-and-forth" movement
characteristic of tremor. In some dystonic patients, tremor-like muscle
spasms or tremulous movements or dystonic tremor may be present upon
attempting to actively resist abnormal, involuntary movements.
Dystonic spasms typically increase in intensity during stress, emotional
upset, or fatigue. Spasms tend to decrease in intensity during periods
of rest or sleep. Many patients temporarily suppress dystonic movements
or spasms by "sensory tricks." These tricks usually consist of touching
the affected or adjacent body parts. Also known as gestes antagonistes,
these sensory tricks are a phenomenon almost unique to dystonia; therefore,
they may play a helpful role in differential diagnosis.
Examples of commonly described sensory tricks include...
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Placing a hand on the side of the face, the chin, or the back of
the head or touching these areas with one or more fingers may
sometimes reduce neck contractions associated with cervical
dystonia. Also known as spasmodic torticollis, cervical dystonia
is characterized by abnormal movements or postures of the neck and
head.
Applying pressure on the eyebrows or touching skin to the side of
the eyes may improve involuntary contractions of eyelid muscles or
blepharospasm.
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Touching the chin or the lips, applying pressure beneath the chin,
or placing an object in the mouth, such as a toothpick, may reduce
dystonia of the jaw, mouth, and lower face (oromandibular
dystonia).
Touching the affected hand with the other hand may help to alleviate
writer's cramp.
Leaning against the wall while standing, pressing on the hips, or
applying pressure to the back of the neck may help to alleviate
dystonia of the trunk (truncal dystonia).
Classification of Dystonia
Dystonia is classified in various ways. The most current, widely accepted
classification consists of three major categories:
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Bodily site(s) of involvement (anatomical distribution)
Age at symptom onset
Cause (etiology) or origin
Anatomical Distribution
Dystonia usually begins in a single body part. It may either remain
restricted to that area or spread to involve another region or regions.
Therefore, it is helpful to classify dystonia based upon anatomical
distribution as follows:
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Focal—limited to one area of the body
Segmental—affecting 2 or more nearby or contiguous areas of the
body
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Multifocal—involving 2 or more distant regions of the body
Hemidystonia—affecting one half of the body
Generalized—leg involvement plus eventual involvement of another
region or regions of the body
Focal Dystonias
There are several forms of focal dystonia as well as other dystonias that
may be limited to one area of the body. Focal dystonias often become
apparent during the fourth or fifth decade, so called adult onset. However,
symptoms may become obvious earlier in life. Overall, women are affected
approximately 3 times more frequently than men.
The symptoms associated with the focal dystonias are variable and depend
upon the intensity and severity of the spasms and the specific body region
and muscle groups involved. The rate of progression from symptom onset
to difficulties in activities of daily living and disability are extremely
variable, ranging from rapid development over days or weeks to a gradual
progression over a decade or more.
Symptoms of focal dystonias may initially be periodic, occurring only
during stressful periods or randomly. At first, symptoms tend to appear
when the affected body part performs certain movements; they typically
disappear when the affected area is at rest. However, as the disease
progresses, dystonic spasms begin to develop with other activities of the
affected region. Symptoms may occur with voluntary actions involving
other bodily areas. This phenomenon is known as overflow. Eventually,
dystonia may be present when the affected part is at rest. Gradually, the
affected area may assume an unusual and sometimes painful posture.
In up to 30 percent of patients, focal dystonias may extend to involve
nearby areas, resulting in segmental dystonia. Less commonly, symptoms
may begin to affect certain non-adjacent regions (multifocal dystonia).
Focal dystonias often stabilize within a few years and may gradually
slightly improve. In addition, some patients may experience a temporary
diminishing or complete remission of symptoms for days or months, usually
within 2 to 3 years following disease onset. Evidence suggests that
remissions most frequently occur in patients with cervical dystonia, as
compared with other focal dystonias.
Focal dystonias are usually considered primary (idiopathic) dystonias,
meaning that dystonia is the only sign, with the possible exception of
tremor, and secondary causes are excluded. Adult-onset focal dystonias
usually occur sporadically, in the absence of a family history. However,
in some relatively rare cases, more than one family member may be affected.
(For further information, see the section entitled "Etiology/ Primary
Dystonia")
Commonly described forms of focal dystonia include...
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Cervical dystonia (spasmodic torticollis)
Blepharospasm
Oromandibular dystonia
Laryngeal dystonia (spasmodic dysphonia)
Limb dystonia
Cervical Dystonia (CD)
Cervical dystonia (CD) is a focal dystonia. It is also known as spasmodic
torticollis and is characterized by abnormal movements or postures of the
neck and head. It is considered the most common form of focal dystonia.
Although CD may become apparent at any age, symptoms usually begin between
the ages 20 to 60 years. Women are affected approximately twice as commonly
as men.
The dystonic spasms of CD affect any combination of neck (cervical)
muscles, resulting in jerky head movements or periodic or sustained
unnatural position of the head . There is also sideways or lateral rotation
of the head and twisting or torticollis of the neck, often with head tilt.
There may be isolated turning, flexing, or extending of the neck to the
side (laterocollis), front (anterocollis), or back (retrocollis). One
shoulder may be elevated and displaced forward on the side toward which
the chin turns. In addition, there is often mild associated dystonia in
the upper arm muscles on the same side (segmental dystonia).
Symptoms of CD often worsen while walking or during stress. Symptoms
typically improve with rest or sleep. In addition, CD is the most common
focal dystonia that responds to sensory tricks. For example, patients with
CD may place their hand on the side of their face, chin, or the back of
the head. This may reduce the intensity of dystonic spasms. Lightly
touching or applying pressure to certain areas of the head on the side
that is opposite to that which the head is turned may temporarily allow
correction of abnormal head position. The reason why sensory tricks work
for some patients is not fully understood.
Over two-thirds of patients, particularly those with sustained head
deviation, have associated neck pain. About one-third also experience
head tremor (i.e., dystonic tremor), hand tremor, or both. Approximately
20 percent of patients with CD also have dystonic spasms of the eyelids
(blepharospasm) or other muscles or of muscle groups of the arm or hand.
Evidence suggests that about 10 percent of those with cervical dystonia
may have brief, spontaneous remissions. An additional 10 percent,
particularly patients with an earlier age at symptom onset, may have
longer remissions of about 2 to 3 years, typically beginning during the
first few years following disease onset.
Blepharospasm
This form of focal dystonia also affects women more frequently than men,
with symptoms typically becoming apparent after age 50. The term
blepharospasm refers to intermittent or sustained closure of the eyelids
due to abnormal, involuntary contractions or spasms of certain muscles
that function to close the eyelids. Some individuals with blepharospasm
experience relatively mild spasms of the muscle underlying the skin of
the eyebrows and the root of the nose as well as of the middle and lower
facial muscles. These spasms may resulting grimacing or facial
distortions. The condition is sometimes called essential blepharospasm
or dystonic blepharospasm.
In some patients, blepharospasm may begin in just one eye (unilateral).
Initial signs of the condition include eye irritation and burning, an
increased sensitivity to light (photophobia), and excessive blinking.
With disease progression, patients may experience narrowing of the
opening of the eyelids due to dystonia muscle contractions; involuntary,
potentially forceful closure of the eyelids; and an inability to
voluntarily raise the eyelids in order to open their eyes.
Excessive blinking and involuntary eyelid closure may be temporarily
relieved by certain sensory tricks, including singing, humming, or
talking; laughing; yawning; opening the mouth; chewing; or applying
pressure on the eyebrows, temple, or skin next to the eyes. These dystonic
spasms generally disappear with sleep. In contrast, symptoms may worsen
with stress, walking, reading, exposure to bright light, looking upward,
watching television, or driving. Accordingly, blepharospasm may cause
varying levels of difficulty with daily tasks, including reading and
driving. Without treatment, blepharospasm often results in functional
blindness, although vision may be normal.
In some patients with blepharospasm, dystonic spasms may extend to nearby
cranial areas, such as muscles of the tongue, mouth, jaw, neck, vocal cords,
or other areas, thus becoming a segmental dystonia. (Also see description
below of Meige syndrome, which involves blepharospasm with lower facial
involvement.)
Oromandibular Dystonia
Oromandibular dystonia (OMD) may be characterized by dystonic spasms
affecting the jaw, mouth, and lower face. The tongue may be involved as
in lingual dystonia. In some cases, this may be the most prominent sign
of OMD.
In patients with OMD, involuntary contractions may involve the muscles
used for chewing (masticatory muscles). These may include the thick muscle
in the cheek that closes the jaw (buccinator muscles) and the broad muscle
that draws back the lower jaw and closes the mouth (temporalis muscle).
Some patients may also experience involuntary contractions of the wide
muscle at the side of the neck that close the jaws. This muscle draws down
the corner of the mouth and lower lip (platysmal muscles) or other muscle
groups.
Associated findings of OMD may include spasms of jaw closure with
difficulty opening the mouth (trismus) and clenching or grinding of the
teeth (bruxism); spasms of jaw opening; or sideways deviation or
protrusion of the jaw. Additional symptoms may also be present, such as
lip tightening and pursing; drawing back (retraction) of the corners of
the mouth; or deviation or protrusion of the tongue. Due to such findings,
OMD may cause jaw pain as well as difficulties eating and speaking
(dysarthria). In addition, in some patients, the dystonic spasms may
sometimes be provoked by certain activities, such as talking, chewing,
or biting. As discussed earlier, particular activities or sensory tricks
may sometimes temporarily alleviate OMD symptoms, including chewing gum,
talking, placing a toothpick in the mouth, lightly touching the lips or
chin, or applying pressure beneath the chin.
Dystonic spasms may extend to involve nearby areas including the muscles
of the eyelids, nose, neck, or vocal cords.
Laryngeal Dystonia
Spasmodic dysphonia or SD is a focal dystonia that affects the vocal cords.
It usually becomes apparent between ages 30 to 50 and affects women more
frequently than men. There are two distinct forms of SD: adductor SD and
abductor SD.
Adductor SD is the more common form of this condition and is characterized
by contraction of certain vocal muscles that draw the vocal cords together
during speech. This causes the voice to have a restricted, strangled, or
hoarse quality. Vocal expression is often interrupted by sudden, short
pauses followed by abrupt bursts of speech, which may become less and less
understandable. In most patients, singing is not as severely affected as
speech.
In abductor SD, contractions of certain muscles that draw the vocal cords
apart causes the voice to have a breathy, whispering quality. Patients
tend to "run out of air" as they attempt to speak and are unable to speak
loudly. As a result, their speech may also be difficult to understand.
Symptom onset is typically relatively gradual. Initial signs often
include increased effort during speech and the loss of voice control that
occurs with emotional stress. The condition tends to stabilize after about
1 to 2 years of increasing symptom severity. Speech may temporarily
improve subsequent to sneezing or yawning. In some patients, sensory
tricks, such as pressing the hand on the abdomen or the back of the head,
may temporarily relieve symptoms.
In up to 30 percent of patients, dystonia may also affect other body
regions, particularly the muscles of the neck or head. In addition, SD
is sometimes associated with dystonic tremor of the vocal cords that may
develop prior to the onset of laryngeal dystonia. Dystonic vocal cord
tremors need to be distinguished from essential tremor (ET), a common
neurologic movement disorder that is often associated with tremor of the
hands or head.
Limb Dystonia
Focal limb dystonia (LD) is associated with dystonic spasms of arm or leg
muscles. These spasms are accompanied by repetitive, twisting movements
or abnormal positions or postures of the affected limb. Limb dystonia may
be segmental, i.e., affecting muscle groups of an arm as well as the neck,
and is also present in those with hemidystonia or generalized dystonia.
Upper limb dystonias often appear only when performing specific tasks.
Thus, these dystonias are often referred to as task-specific dystonias.
The most common task-specific limb dystonia of the arm occurs with writing
and is therefore known as writer's cramp.
Writer's cramp (WC) typically affects the person's dominant side, meaning
the "writing hand." It is often characterized by an abnormally pronounced,
forced grip on the writing instrument. This may occur immediately upon
grasping the pen or pencil or shortly after beginning to write. Less
commonly, there may be excessive extension of the fingers that causes the
writing instrument to drop from the hand. Additional findings may include
exaggerated flexion or extension of the affected wrist, forcing the palm
of the hand downward or upward. In some patients, dystonic spasms may also
extend to involve certain muscles of the arm and shoulder, potentially
resulting in elevation of the elbow and outward extension of the shoulder.
Writing may be labored and shaky with discomfort or pain in the forearm.
Some individuals are not able to write–even after just a few words.
Touching or stabilizing the affected hand with the other hand may help
to alleviate symptoms.
In approximately one-third of patients with writer's cramp, dystonic
spasms may eventually occur with tasks other than writing. In about 25%
who attempt to write with the uninvolved hand, writer's cramp may extend
to the previously unaffected hand (bilateral WC).
In some patients, dystonic spasms may eventually affect adjacent or other
body regions. In addition, writer's cramp is often associated with hand
tremor that may occur with writing (action tremor) or while holding the
hand in a fixed position against gravity (postural tremor).
Other focal task-specific limb dystonias have also been described that
may affect...
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Musicians. Characteristic task-specific dystonias (TSDs) have been
reported among pianists, guitarists, and clarinetists. TSDs may
affect musicians using almost any type of instrument.
Participants in certain sports. For example, TSDs have been
described in golfers (a TSD known as the "yips"), tennis players,
and dart throwers.
Workers in certain occupations, such as seamstresses, shoemakers,
or milkers.
Generally, activities that may provoke certain TSDs include those
requiring highly specialized, precise actions or extremely repetitive
movements. Although most TSDs affect the upper limbs, they have rarely
been described in the lower limbs, such as among dancers, or cyclists.
Lower limb dystonia is a focal dystonia that may primarily affect the ankle
and foot, often resulting in inward turning of the heel with upward bending
of the sole of the foot. The dystonic spasms initially occur only with
walking (action dystonia). However, the dystonia may gradually be present
at rest and eventually lead to sustained, fixed postures. Lower LD that
appears during childhood is usually associated with the onset of
generalized dystonia. However, lower LD that initially becomes evident
during adulthood is rare. In such cases, experts indicate that diagnostic
evaluations should be conducted to determine whether lower limb dystonia
is present secondary to Parkinson's disease, parkinsonism syndromes, or
other underlying causes.
Other Focal Dystonias
Rare forms of focal, typically adult-onset, dystonia have been described,
including the following:
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Truncal dystonia. Dystonic spasms may cause unusual stretching,
bending, or twisting of the trunk, sometimes accompanied with
sideways curvature of the spine (scoliosis). At symptom onset, the
spasms may occur only with standing or walking. Eventually,
symptoms may also be present during rest. Dystonic spasms may
eventually extend to involve adjacent regions, such as muscles of
the upper arms or legs or the pelvis.
Abdominal wall dystonia. Also known as "belly-dancer's
dyskinesia," this condition is characterized by sustained
contractions and involuntary, writhing movements of the abdominal
wall.
Segmental Dystonia
As many as 30 percent of patients with a primary focal dystonia experience
dystonic spasms in areas next to the primary site. When dystonia affects
two areas of the body that are next to each other, this is termed segmental
dystonia. Dystonic spasms affect at least 2 adjacent areas of the body,
such as facial and neck muscles ; muscle groups of the neck and upper arm;
or trunk and leg muscles.
One common segmental dystonia involves muscles of the eyelids, jaw, mouth,
and lower face. Known as Meige syndrome, the condition is characterized
by periodic or sustained closure of the eyelids (blepharospasm). Eyelid
closure is accompanied by forceful spasms of jaw opening or closure,
clenching or grinding of the teeth, sideways displacement of the jaw, lip
tightening and pursing, and tongue protrusion . In addition, this form
of segmental dystonia may spread to neck muscles or other muscle groups.
Meige syndrome more frequently affects women than men and typically
becomes apparent during the sixth decade of life.
Multifocal Dystonia
If a focal dystonia spreads to involve an additional area of the body,
it usually affects an adjacent area (segmental dystonia). Less commonly,
dystonic spasms may begin to affect a non-adjacent region or regions,
resulting in signs of multifocal dystonia. In those with multifocal
dystonia, the dystonia involves two or more non-adjacent areas of the body,
such as both legs; one or both arms and a leg; or the face and a leg.
Hemidystonia
Hemidystonia is a form of dystonia that affects one side of the body or
is characterized by unilateral involvement of the upper and lower limbs.
It is considered a type of multifocal dystonia. Hemidystonia typically
occurs secondary to certain underlying conditions, particularly multiple
sclerosis, tumor, stroke, or vascular malformations.
Generalized Dystonia
In patients with generalized dystonia, dystonic spasms involve the legs
or one leg and the trunk as well as one other area of the body. Unlike
primary focal dystonias, primary generalized dystonia is typically
associated with a younger age at symptom onset (early onset). "Primary
dystonia" indicates that dystonia is the essential or principal finding,
with the possible exception of tremor, and that a secondary cause is
excluded.
Dystonia: Age of Onset
The age at symptom onset of primary dystonia is an important indicator
of whether the dystonia will potentially progress to involve other body
regions. Generally, the younger the patient at symptom onset, the greater
the likelihood that dystonia will gradually affect multiple areas of the
body. In patients with early-onset primary dystonia, the dystonia usually
starts in a leg or arm and progresses to affect other limbs and the trunk.
In addition, early onset with initial involvement of a leg is also
considered an important indicator suggesting eventual progression to
generalized dystonia.
In contrast, the older the patient at symptom onset, the greater the
likelihood that the dystonia will remain localized , potentially with
limited involvement of adjacent regions. In patients with primary
late-onset dystonia, the dystonia often begins in the upper body, such
as the neck, head and/or neck, or an arm.
Dystonia may be classified based upon age of onset as follows:
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Childhood onset—0 to 12 years
Adolescent onset—13 to 20 years
Adult onset—older than 20 years
The broader term early onset generally refers to dystonia that develops
before age 21; however, the late twenties have also been suggested to be
early onset. "Late onset" indicates symptom onset later than age 20 or
the late twenties.
Dystonia: Cause
Dystonia may be further classified based upon its cause. More specifically,
dystonia may be categorized according to its causes as follows:
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Primary (idiopathic) dystonia—dystonia is the only sign and a
secondary cause is ruled out.
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Secondary (symptomatic) dystonia—dystonia results primarily from
environmental causes, underlying disease, which may or may not be
genetic, or injury to the brain.
Dystonia-plus syndromes—this classification refers to
nondegenerative, neurochemical disorders in which dystonia is
associated with other neurologic features, such as myoclonus or
parkinsonism.
Heredodegenerative dystonia—this category refers to usually
hereditary, neurodegenerative disorders in which other neurologic
symptoms are present in addition to dystonia.
Primary (Idiopathic) Dystonia
In patients with primary dystonia, dystonia occurs as the only symptoms
with the possible exception of tremor. The primary dystonias are
frequently described as "pure dystonias." Primary dystonias were often
referred to as "idiopathic torsion dystonia" or ITD, with the term
"idiopathic" meaning "of unknown cause or etiology." However, because
disease genes have been identified as an underlying cause, most experts
now recommend using the term "primary." The word "torsion," which is still
in use, refers to the twisting nature of the abnormal movement patterns
seen in dystonia.
Primary dystonia may be familial or appear to occur in the absence of a
family history (sporadic). The primary dystonias include several genetic
disorders, some of which have been linked to changes (mutations) of
specific genes mapped in some families to a particular chromosome. However,
most primary dystonias are sporadic, have adult onset, and are focal or
segmental in nature.
Certain primary dystonias have been mapped to particular genes. These
include...
Dystonias Caused by DYT1 Gene
Mutation
Most cases of early-onset primary dystonias, which may become symptomatic
during childhood or early adulthood, are due to mutations of a gene known
as DYT1. This gene has been mapped to the long arm of chromosome 9 at 9q34.1.
This form of primary dystonia is also known as Dystonia musculorum
deformans (DMD). Other forms of DYT1 dystonia include...
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Early-onset primary dystonia
Idiopathic torsion dystonia (ITD)
Primary torsion dystonia
Primary generalized dystonia
To avoid confusion with other primary dystonias, researchers suggest that
this form of the disorder should be referred to as DYT1 dystonia or
Oppenheim dystonia, after the researcher who first identified the
disease.
The mean age of onset of DYT1 dystonia is approximately 12 years. Symptoms
rarely begin after the age of 29 years. In approximately 90 to 95 percent
of cases, symptoms begin in a leg or an arm, and then spread to other
regions of the body. Patients whose symptoms initially involve a leg tend
to have an earlier age of onset than those whose symptoms initially affect
an arm. Symptom onset involving a leg is also associated with an increased
likelihood that the condition will evolve to generalized dystonia. The
rate of progression to generalized dystonia typically occurs more quickly
in patients with leg onset compared to those with initial arm involvement.
Although the rate of progression is extremely variable from patient to
patient, it usually is more rapid within the first 5 to 10 years following
symptom onset.
For patients with initial arm involvement, dystonic spasms first appear
when performing specific activities, such as writing or playing a musical
instrument. As the disease progresses, dystonic symptoms occur with other
unrelated activities of the arm and be provoked by the actions of other
body parts. This phenomenon is known as overflow. In some affected
individuals, walking causes the arm to move backward behind the body.
Eventually, dystonia may be present even when the arm is at rest,
potentially leading to a sustained, twisted position or posture. For those
with symptom onset in the arm, dystonia tends to progress to the other
arm or nearby areas of the upper body and neck. There is about a 50 percent
chance of progression to generalized dystonia.
In contrast, for patients with initial leg involvement, there is an
approximate 90 percent chance of progression to generalized dystonia.
Those with leg onset develop distinctive gait abnormalities, such as
unusual twisting or swinging of the leg as it is moved forward; however,
these symptoms may not occur with other activities, such as dancing,
running, or walking backward. The hip may also be extended or abducted
in an outward position. The foot may swing and elevation or extension of
the knee may be present. In some patient, inward turning of the heel and
upward bending of the sole of the foot (equinovarus deformity) is
associated with difficulty positioning the heel on the ground. In addition,
severe flexion of the trunk may result in a "bent over" posture with
extension of the neck. As the disease progresses, dystonic spasms occur
with less specific activities of the leg and are triggered by actions of
other parts of the body (overflow). Eventually, symptoms are present even
when the leg is at rest, resulting in abnormal, sustained positions or
postures.
As DYT1 dystonia progresses, symptoms may spread to involve other areas
of the body, particularly in those patient with initial leg involvement.
The dystonia may eventually become segmental and then generalized in
nature, with distortion of affected regions. In such cases, associated
findings may include...
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Involvement of the neck (cervical dystonia or CD), including jerky
head movements. The head may become temporarily tilted or twisted
(torticollis) in a sideways, forward, or backward position. These
episodes may become more sustained as the disease progresses.
Twisting movements or abnormal posturing of the upper body and
severe bending of this area. This posturing may result in a fixed
sideways curvature of the spine, known as scoliosis. In addition,
there may be pronounced inward spinal curvature of the lower back,
known as lordosis as well as twisting of the pelvis.
Difficulty walking or eventually the inability to walk, in some
cases.
In rare cases, difficulties in speech or dysarthria may develop along with
facial grimacing. However, the throat (pharynx), vocal cords, face, and
tongue, tend to remain unaffected.
The DYTI gene
DYT1 dystonia is an autosomal dominant disorder, meaning that it may be
manifested in some individuals who have a single copy of the mutated DYT1
gene. However, the disorder has reduced penetrance. In other words, not
all individuals who carry the gene mutation will develop DYT1 dystonia.
Evidence suggests that 30 to 40 percent of those with the mutated DYT1
gene have symptoms of the disorder; thus, most people with the mutated
gene do not develop symptoms of dystonia.
Although most individuals with DYT1 dystonia are affected by early
limb-onset dystonia, disease severity may vary greatly from patient to
patient. In other words, the DYT1 gene has variable expressivity, meaning
that the symptoms vary in range and severity.
Some individuals with DYT1 dystonia have no apparent family history of
the disorder. This may be explained by low penetrance of the gene in other
family members who are carriers or by the variable expression of the
condition. Therefore, the disease may remain undiagnosed in mildly
affected family members. Other evidence suggests that the disorder
results from a new genetic mutation that occurs randomly for unknown
reasons (sporadically).
The underlying cause or causes of the gene's low penetrance and variable
expressivity remain unknown. Various mechanisms may play some role. These
include the interaction of other genes that modify or change the activity
of other genes, genetic anticipation, or other genetic factors.
Environmental influences may also play a role, including trauma, such as
injuries to the arms, legs, or head. Symptoms may begin or worsen in a
previously injured part of the body. Peripheral injury may influence
functioning of the basal ganglia and its pathways and play some role in
"triggering" symptom onset in certain individuals who have a mutated DYT1
gene.
The mutation responsible for DYT1 dystonia is deletion of one of a pair
of certain basic chemical "building blocks" of DNA known as guanine,
adenine, and guanine (GAG trinucleotides) in the DYT1 gene's coded
instructions. The DYT1 gene regulates or "encodes" production of a protein
known as torsinA. Although the protein's specific function is unknown,
it appears to be related to a class of proteins (heat-shock proteins) that
enable cells to recover from injury or stress. TorsinA is found in neurons
throughout the brain.
Most ethnic populations are affected by DYT1 dystonia. However, the
disorder is most common among individuals of European Ashkenazi Jewish
descent. (For further information, please see the section entitled
"Epidemiology.") The DYT1 gene mutation is responsible for most cases of
early limb-onset primary dystonia in Jewish families (kindreds). Genetic
analysis of affected Ashkenazi kindreds has shown that these families
share a common set of genes (known as a haplotype) that are closely linked
to the DYT1 gene (on chromosome 9q) and typically inherited with it as
a unit. (Such sharing of a specific haplotype more commonly than normally
expected by chance is known as "linkage disequilibrium.") Experts
indicate that the association of the linked genes with DYT1 suggests that
the disorder is largely due to a single mutation event in the past (founder
mutation). It has been calculated that the original or founder mutation
was introduced into the Ashkenazi Jewish population approximately 350
years ago in Lithuania. Genetic analysis has revealed that the DYT1
disease gene also appears to be responsible for most cases of early
limb-onset primary dystonia in non-Jewish kindreds. However, such
investigation has not revealed a common set of closely linked genes (i.e.,
linkage disequilibrium) to suggest a single founder mutation in these
non-Jewish families.
In a study of 174 Ashkenazi individuals with early- or late-onset primary
dystonia, more than 90 percent of those with isolated or familial early
limb-onset dystonia carried the chromosome 9q haplotype. Most of these
patients had progression to multifocal or generalized dystonia. In
contrast, those who did not carry the haplotype comprised the majority
of patients who had late-onset dystonia with initial involvement of head
or neck (cervical) muscles rather than limb muscles. In almost all of these
patients, the dystonia remained focal or segmental. Thus, such evidence
suggests that a single mutation event is responsible for most cases of
early limb-onset dystonia in individuals of Ashkenazi descent, yet is not
the cause of primary adult-onset cervical dystonia. Rather, researchers
indicate that the latter may result from either DYT1 mutations, other
dystonia genes, and/or other factors. In at least some families, evidence
suggests that late-onset and cervical- or cranial-onset primary
dystonia–or, more rarely, late-onset dystonia that also involves the
legs or trunk–is due to mutation of other dystonia genes.
Accordingly, following is a description of primary dystonias that have
been mapped to genes other than the DYT1 gene (or simply excluded from
the DYT1 gene) in certain families.
DYT6 Dystonia
DYT6 dystonia is an autosomal dominant primary dystonia that has been
mapped to chromosome 8 (8p21q22). The disorder has been described in
members of 2 large Mennonite families (kindreds). Affected members of
these kindreds have been shown to share a common set of genes (haplotype)
closely linked to DYT6, suggesting a shared mutation in the past. Symptoms,
which may become apparent in either childhood or adulthood, may initially
affect muscles of the limbs or the neck (cervical) regions. In almost all
affected members, there has been extension of the dystonia from the
initial site of involvement to multiple body regions, with most affected
by dystonia of limb, head, and cervical regions. Reports suggest that the
most disabling feature of the disorder often consists of severe
difficulties articulating speech (dysarthria).
DYT7 Dystonia
Several families have been described with autosomal dominant, adult-onset,
primary dystonia that is focal in distribution, affecting the neck region
(known as familial torticollis). In a German kindred, the autosomal
dominant disorder has been mapped to chromosome 18p. This genetic location
(locus) has been designated as DYT7. However, other kindreds with familial
torticollis have been excluded from the DYT7 (as well as the DYT1) regions
and the responsible gene location has not yet been identified.
Other Familial Primary Dystonias
Additional families have also been described with autosomal dominant
primary dystonias that have been excluded from the DYT1 region. These
include kindreds with a form of primary dystonia that usually initially
affects the neck (cervical) region, often spreads to involve head, and,
in some instances, affects the arm. In addition, the dystonia has become
generalized in a few cases. Symptom onset has occurred during childhood
or adulthood. This type of dystonia, sometimes described as "familial
cervical-cranial predominant dystonia," has been reported in some
non-Jewish families, including Italian and North American kindreds.
Research is ongoing to determine additional genes, specific gene
mutations, and/or environmental factors that may play some role in causing
primary dystonia in certain families.
Other familial primary dystonias that have been given specific "genetic
designations" include the following:
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DYT2: This genetic designation has been reserved by experts for any
possible autosomal recessive form of familial primary dystonia.
However, none has been confirmed to date.
DYT4: This refers to an autosomal dominant primary dystonia in a
large, multigenerational Australian kindred affected by abductor
("whispering") spasmodic dysphonia (laryngeal dystonia). Although
the dystonia first involved speech in most affected family members,
a few initially were affected by dystonia of the neck region, later
developing dysphonia. (For further information, see the section
entitled "Anatomical distribution, focal dystonia, laryngeal
dystonia.")
Researchers expect that additional familial primary dystonias will be
described that may map to other, currently unknown genetic loci. (For
further information on dystonias that have been given specific genetic
designations, please see the section entitled "Genetic Designations for
the Dystonias.")
Primary Adult-onset Focal/Segmental
Dystonias
As discussed earlier, focal dystonia refers to dystonia that is limited
to a single region of the body. In some patients, focal dystonias may
extend to involve adjacent areas, resulting in segmental dystonia.
Primary focal dystonia is most commonly of adult onset, often becoming
apparent during the fourth or fifth decade of life.
The cause of primary adult-onset focal dystonia is usually unknown, with
the condition appearing to occur in the absence of a family history
(sporadically). Rarely, however, more than one family member may be
affected. For example, as mentioned earlier, a gene location (designated
DYT7) for adult-onset primary dystonia predominantly affecting the neck
region (familial torticollis) has been mapped to chromosome 18p in a
German family.
However, in most cases, the role of heredity in primary adult-onset
focal/segmental dystonia remains unknown. Yet some experts suggest that
heredity may be a factor in the development of these dystonias, based upon
several findings, such as the following:
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In addition to the kindreds discussed above, familial cases of
primary adult-onset focal dystonia have been reported, including
cervical dystonia, writer's cramp, and orofacial dystonia.
In one study, 25 percent of 40 non-Jewish individuals with focal
dystonia (e.g., cervical dystonia, cranial dystonias, writer's
cramp) had relatives with symptoms of dystonia.
According to multiple large studies of primary adult-onset focal
dystonia, 2 to 15 percent of patients have had relatives with signs
of focal or segmental (but not generalized) dystonia.
Based upon these and other findings, some researchers suggest that primary
adult-onset focal dystonias may commonly be transmitted as an autosomal
dominant trait with reduced penetrance and variable expressivity. In
addition, some investigators speculate that adult-onset primary focal
dystonias may represent a localized manifestation of primary generalized
dystonia, with the final anatomical distribution reflecting patient age
and specific site of onset. Possible support for this theory includes the
fact that primary generalized dystonia often begins as a focal dystonia.
In addition, primary focal and generalized dystonias are both
characterized by effective "sensory tricks" and both respond similarly
to certain medications. Yet, as mentioned earlier, dystonia that begins
in the neck or cranial region rarely results from mutations of the DYT1
gene, indicating that most focal dystonias that do not begin in a limb
are probably distinct from primary generalized dystonia. Therefore,
whether primary focal and generalized dystonias may be variations of the
same disorders or are truly distinct disease entities remains unclear.
Some studies also suggest that focal dystonia may be precipitated by
trauma and/or overuse of the affected bodily region (i.e., peripheral
factors). As mentioned earlier, some investigators theorize that prior
trauma may play some role in triggering disease onset in patients who carry
a mutated DYT1 gene for DYT1 dystonia. In addition, several studies have
suggested a possible association of focal dystonias with prior peripheral
trauma. For example, researchers have reported that...
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Trauma occurred 3 to 6 months prior to symptom onset in
approximately 5 to 12 percent of patients with cervical dystonia.
Inflammation of the vocal cords (laryngitis) has occurred prior to
the onset of laryngeal dystonia in some patients.
Writer's cramp has sometimes occurred subsequent to localized hand
injury.
Oromandibular dystonia (OMD) has been described following dental
treatment.
In some cases, the relationship between trauma and the onset of dystonia
is clear when dystonia follows brain injury or severe peripheral trauma.
(For further information, please see the section entitled
"Etiology/Secondary Dystonia.") However, researchers indicate that, in
many instances, the relationship is less clear and trauma alone probably
would not be sufficient for the development of dystonia. Rather, they
suggest that trauma may play some role in triggering dystonia in those
with previously, very mild, undetectable cases–or in patients with an
existing, potentially genetic, susceptibility to the disorder. Further
research is necessary to determine the various underlying genetic,
environmental, and/or other underlying mechanisms that may play a role
in causing the primary dystonias. (For more information, please see the
section entitled "Pathophysiology.")
Secondary (Symptomatic) Dystonia
Secondary dystonia refers to dystonia that results primarily due to
environmental factors or "insults" that affect the brain. In addition,
spinal cord or peripheral injury may also be responsible for secondary
dystonia. Causes of secondary or symptomatic dystonia include the
following:
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Abnormalities of brain function due to insufficient oxygen supply
to tissues shortly before, during, or after birth (perinatal
cerebral anoxia), such as cerebral palsy
Vascular malformations of the brain in which a tangle of abnormal
blood vessels form communications between the arterial and venous
systems (arteriovenous malformations)
Brain tumors
Brainstem lesions
Head injury
Inflammatory, infectious, and postinfectious conditions affecting
the brain (encephalitis), such as Reye syndrome, Creutzfeldt-Jakob
disease (CJD), and human immunodeficiency virus (HIV) infection
Stroke or localized brain damage due to temporary interruption of
its blood supply or leakage of blood outside blood vessel walls
(cerebral infarction or hemorrhage)
Multiple sclerosis (MS), a progressive disease of the central
nervous system characterized by loss of myelin
Thalamotomy, a procedure involving surgical destruction (ablation)
of a selected region of the thalamus, which is a paired structure
deep in the brain involved in regulating movement. This procedure
has been used to help treat certain neurologic movement disorders,
including Parkinson's disease, essential tremor, and dystonia.
Injury or lesions of the spinal cord within the neck region
(cervical spinal cord)
Narrowing (stenosis) of the spinal canal within the lower back
region (lumbar canal stenosis). (The spinal canal is the cavity
within the spinal column that contains the spinal cord.)
Peripheral trauma, which may be followed by focal dystonia in the
affected body part
Certain metabolic conditions, such as hypoparathyroidism, which is
characterized by decreased activity of the parathyroid glands
Prolonged or substantial exposure to toxic environmental agents,
such as carbon monoxide, cyanide, manganese, or methanol
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Therapy with certain medications, such as the following:
o Particular anticonvulsant medications, including phenytoin
(Dilantin®) or carbamazepine (Tegretol®)
o Dopamine receptor blockers (antagonists), such as certain
antipsychotic drugs, including haloperidol (Haldol®);
antidepressants, such as amoxapine (Asendin®); antinausea
(antiemetic) medications, such as prochlorperazine
(Compazine®) or metoclopramide (Reglan®); or other agents.
In some patients, therapy with certain dopamine receptor
blockers may result in a sudden (acute) onset of dystonia or
the development of persistent dystonia known as tardive
dystonia.
o Levodopa (L-dopa), a precursor of the neurotransmitter
dopamine, for the treatment of parkinsonism
Psychogenic changes in which symptoms have a mental or an emotional
basis rather than an organic origin
Secondary dystonia most commonly results from therapy with dopamine
receptor antagonists (i.e., tardive dystonia). In adults, tardive
dystonia is often focal or segmental in nature and may sometimes be
difficult to distinguish from primary adult-onset dystonias,
necessitating a careful patient medication history. For example, tardive
dystonia often initially involves muscles of the face or neck and may
resemble oromandibular/lingual dystonia or other primary adult-onset
focal dystonias. Involvement may remained confined to the initial site
or become segmental, affecting the arms and trunk. In children, however,
tardive dystonia is more likely to be generalized in nature, involving
limb and trunk muscles.
Other common causes of secondary dystonia include perinatal cerebral
anoxia, psychogenic causes, stroke, or inflammatory conditions of the
brain (encephalitis). In addition, as mentioned above, researchers
continue to question the relationship between injury and the development
of dystonia in some cases, such as the potential role peripheral trauma
may play in "triggering" dystonia onset in patients who carry a copy of
the mutated DYT1 gene. (For further information, see the section entitled
"Etiology/Primary Dystonia.") However, evidence suggests that the
relationship between injury and secondary dystonia is sometimes clear,
such as due to localized brain injury or severe peripheral trauma. In those
with apparent, peripherally induced dystonias, the region injured is
usually the area that develops dystonia. For example, blepharospasm has
been reported following localized eye disease and cervical dystonia has
developed subsequent to whiplash. Experts indicate that peripherally
induced dystonias may tend to differ from other secondary dystonias in
some areas, such as the following:
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A relatively short period between the event and symptom onset. In
contrast, dystonia that occurs secondary to localized brain lesions
sometimes may not develop for long periods. For example, children
who had insufficient oxygen supply to the brain during birth may
not develop associated dystonia for several years, such as when they
are approximately 7 or 8 years of age.
From the onset of symptoms, dystonia present during periods of rest
Persists during sleep
Limited range of movement and fixed postures
Potentially associated with development of pain (causalgia or
reflex sympathetic dystrophy)
Absence of temporary improvement with "sensory tricks" (i.e., no
gestes antagonistes)
(For more information on the potential relationship between trauma and
the development of dystonia, please see the section entitled
"Pathophysiology.")
Signs Potentially Suggestive of
Secondary Dystonia
Evidence suggests that the relative association between age at symptom
onset and disease course is somewhat different for those with secondary
dystonia in comparison to patients with primary dystonia. For example:
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Generally, for those with primary dystonia, the younger the patient
at symptom onset, the greater the likelihood that the dystonia will
become generalized. However, secondary dystonia beginning during
adulthood is more likely to generalize than in those with
adult-onset primary dystonia.
A relatively higher percentage of patients with secondary dystonia
seem to have early symptom onset or a form of generalized dystonia.
In addition, according to experts, there are a number of factors that may
suggest that dystonia is secondary rather than primary. Such factors may
include the following:
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Patient history of a possible causative (etiologic) factor, such
as exposure to certain medications or toxins; perinatal cerebral
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anoxia; inflammatory conditions of the brain (encephalitis); or
head, spinal, or peripheral trauma
Dystonia that occurs in association with other neurologic signs,
such as symptoms of parkinsonism, including rigidity, slowness of
movement (bradykinesia), and postural instability; myoclonus;
sudden episodes of uncontrolled electrical activity in the brain
(seizures); certain eye (ocular) abnormalities; muscle weakness;
impaired coordination of voluntary movements (ataxia); spasticity;
dementia; or other findings
Dystonia that occurs during periods of rest, rather than during
voluntary action. Primary dystonia typically initially occurs with
certain voluntary movements (action dystonia); in contrast, some
secondary dystonias may initially be characterized by dystonia of
the affected body part at rest (rest dystonia.
Initial leg involvement during adulthood. (As noted previously,
lower limb dystonia that initially becomes evident in an adult is
extremely rare. Thus, in such cases, diagnostic evaluations should
be conducted to determine whether the condition has occurred
secondary to Parkinson's disease, other parkinsonism syndromes, or
other underlying conditions.)
Hemidystonia. (Evidence suggests that a significantly higher
percentage of patients with secondary dystonia develop
hemidystonia compared with those affected by primary dystonia.)
Early onset of speech involvement in association with dystonia
Abnormal laboratory test results
Abnormal neuroimaging results, such as based upon computed
tomography (CT) scanning or magnetic resonance imaging (MRI)
Signs suggestive of psychogenic causes, such as an abrupt onset,
spontaneous remissions, disappearance of dystonic movements with
distraction, etc.
Drugs That May Cause Dystonia
Drugs belonging to a class called "dopamine receptor blocking agents"
(DRBAs) can cause dystonia. The following is a list of such drugs that
can cause dystonia.
Generic
(Trade Names)
Acetophenazine
(Tindal®)
Amoxapine
(Asendin®)
Chlorpromazine
(Thorazine®)
Fluphenazine
(Permitil®, Prolixin®)
Haloperidol
(Haldol®)
Loxapine
(Loxitane®, Daxolin®)
Mesoridazine
(Serentil®)
Metaclopramide
(Reglan®)
Molindone
(Lindone®, Moban®)
Perphenazine
(Trilafon® or Triavil®)
Piperacetazine
(Quide®)
Prochlorperazine (Compazine®, Combid®)
Promazine
(Sparine®)
Promethazine
(Phenergan®)
Thiethylperazine (Torecan®)
Thioridazine
(Mellaril®)
Thiothixene
(Navane®)
Trifluoperazine (Stelazine®)
Triflupromazine (Vesprin®)
Trimeprazine
(Temaril®)
Dystonia-plus Syndromes
Experts established the "dystonia-plus syndrome" etiologic
classification to help differentiate dystonic disorders that are distinct
from primary (idiopathic) dystonias; secondary (symptomatic) dystonias;
and neurodegenerative, usually hereditary (heredodegenerative)
disorders in which other neurologic signs are typically present. In
contrast, the dystonia-plus syndromes include nondegenerative,
neurochemical disorders characterized by dystonia as well as additional
neurologic features, such as myoclonus or parkinsonism. Myoclonus is
characterized by sudden, involuntary, "shock-like" muscle contractions.
In addition, these brief, jerk-like movements are often accompanied by
periodic interruptions in voluntary muscle contraction (muscle
inhibition), leading to lapses of sustained posture. Signs of
parkinsonism include slowness of movement (bradykinesia), rigidity,
postural instability, and tremor at rest. Dystonia-plus syndromes
currently include the following:
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Dopa-responsive dystonia (DRD) or Segawa syndrome
Rapid-onset dystonia-parkinsonism (RDP)
Myoclonus-dystonia
Dopa-responsive Dystonia
Also known as Segawa syndrome, dopa-responsive dystonia (DRD) is a genetic
disorder that typically becomes apparent from approximately age 6 to 16.
Girls are affected about 2 to 4 times more frequently than boys. Evidence
suggests that approximately 10 percent of patients with childhood-onset
dystonia are affected by DRD.
In many patients, onset is characterized by an abnormal, "stiff-legged"
manner of walking (gait), with upward bending of the sole of the foot
(plantar flexion) or turning of the foot outward at the ankle (eversion)
and a tendency to walk on the toes. Dystonia may also extend to involve
muscles of the arms, trunk, and, less frequently, the neck. In addition,
DRD is typically characterized by signs of parkinsonism that may be
relatively subtle. Such signs may include slowness of movement
(bradykinesia), stiffness and resistance to movement (rigidity), balance
difficulties, and postural instability. Approximately 25 percent also
have abnormally exaggerated reflex responses (hyperreflexia),
particularly in the legs.
Many patients experience improvement with sleep, are relatively free of
symptoms in the morning, and develop increasingly severe symptoms as the
day progresses (i.e., diurnal fluctuation). Accordingly, this disorder
has sometimes been referred to as "progressive hereditary dystonia with
diurnal fluctuations." Yet some DRD patients do not experience such
diurnal fluctuations, causing many researchers to prefer other disease
terms.
For example, in those with DRD, symptoms typically dramatically improve
with low-dose administration of levodopa (L-dopa), an amino acid that is
a biologic "forerunner" or precursor of the neurotransmitter dopamine.
(Neurotransmitters are naturally produced chemicals that may transfer
nerve impulses across the spaces between neurons, enabling nerve cells
to communicate.) Low-dose L-dopa usually results in near-complete or
total reversal of all associated symptoms for these patients. In addition,
the effectiveness of such therapy is typically long term, without the
complications that often occur for those with Parkinson's disease who
undergo L-dopa treatment. Thus, most experts indicate that this disorder
is most appropriately known as dopa-responsive dystonia (DRD).
DRD is an autosomal dominant disorder that usually appears to result from
mutations of a gene known as guanosine triphosphate (GTP) cyclohydrolase
I (GCH1 or DYT5). The GCH1 gene, which has been mapped to chromosome
14q22.1, regulates production of an enzyme that speeds (catalyzes) the
first step in the "building up" of a compound (i.e., the cofactor
tetrahydrobiopterin) required for tyrosine hydroxylase and other enzymes.
In turn, these enzymes are required for the production (synthesis) of
certain neurotransmitters, such as dopamine. In patients with DRD, there
are significantly reduced dopamine concentrations in substructures of the
basal ganglia collectively known as the striatum. (As mentioned earlier,
the basal ganglia are specialized nerve cell clusters deep within the
brain that play an essential role in regulating motor behavior.)
As with DYT1 dystonia, DRD has reduced penetrance and variable
expressivity. In other words, evidence suggests that only about 30 to 40
percent of those who carry a copy of the disease gene manifest symptoms.
In addition, the severity of associated symptoms may vary greatly from
patient to patient, including among affected members of the same family
(kindred).
Related genetic disorders have been described that may result in similar
symptoms and signs (phenotype), with improvement from therapy with L-dopa
or certain agents that produce dopamine-like effects (dopamine agonists).
For example...
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A rare autosomal recessive disorder has been reported in which
mutation of the gene that regulates production of tyrosine
hydroxylase (see above) results in symptoms similar to those of DRD.
Such symptoms also respond to L-dopa therapy. In patients with this
disorder, signs of dystonia and parkinsonism typically begin during
infancy or early childhood.
Several autosomal recessive disorders have also been described in
which biopterin deficiency is associated with dystonia,
parkinsonism, as well as signs resulting from decreased levels of
the neurotransmitters serotonin and norepinephrine. These may
include rigidity, chorea, myoclonus, temperature disturbances,
sudden episodes of uncontrolled electrical activity in the brain
(seizures), contraction of the pupils (miosis), and abnormally
increased levels of the amino acid phenylalanine in the blood
(hyperphenylalaninemia). Patients with these disorders may have
partial response to therapy with L-dopa.
Another variant of DRD is an autosomal recessive disorder
characterized by deficiency of the enzyme aromatic amino acid
decarboxylase, which speeds the conversion of levodopa to dopamine.
Associated symptoms become apparent during infancy. Such findings
may include dystonia, parkinsonism, excessive sweating
(hyperhidrosis), diminished muscle tone (hypotonia), feeding
difficulties, drooping of the upper eyelids (ptosis), and
contraction of the pupils (miosis). There may also be episodes of
sudden, transient, involuntary movements; in which the eyes are
held in a fixed position, such as up, down, or sideways, potentially
with spasms or closure of the eyelids (oculogyria); and/or of
periods of deep sleep. Symptoms respond to therapy with dopamine
agonists and monoamine oxidase inhibitors.
Rapid-onset Dystonia-parkinsonism
Rapid-onset dystonia-parkinsonism (RDP) is an autosomal dominant
disorder that has been mapped to chromosome 19q (DYT12). Symptom onset
may occur during childhood, adolescence, or adulthood. RDP is
characterized by the abrupt development over hours, days, or weeks of
combined dystonia and parkinsonism. In many cases, the sudden onset or
worsening of symptoms may develop following certain stressful events,
such as exposure to extreme heat, running, childbirth, or fever. In
patients with RDP, findings may include the following:
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Dystonic movements or postures of the limbs, with the arms typically
more affected than the legs
Poverty of movement (bradykinesia)
Impaired articulation of speech (dysarthria)
Difficulties swallowing (dysphagia)
Postural instability
Reports indicate that some members of affected kindreds may have an
isolated, relatively mild, intermittent limb dystonia of the hand and/or
foot that may remain unchanged or may be present years before the sudden
onset of combined dystonia-parkinsonism. Diagnostic testing may reveal
abnormally low levels of homovanillic acid (HVA) in the cerebrospinal
fluid (CSF). Homovanillic acid is produced by normal metabolism of the
neurotransmitter dopamine. Depleted levels of HVA may be detected in
affected individuals, those who carry a copy of the mutated gene yet have
no associated symptoms (asymptomatic carriers), or unaffected
individuals with a symptomatic sibling or parent (at-risk individuals).
In contrast to DRD, treatment with L-dopa or dopamine agonists provides
only minimal benefit.
Because neuroimaging techniques have not detected pathologic
abnormalities in RDP, this disorder is often classified as a dystonia-plus
syndrome. However, as neuropathologic studies become available, some
investigators suspect that it may be shown to be neurodegenerative in
nature and thus may be more appropriately classified as a
heredodegenerative dystonia. (For further information, please see the
section entitled "Etiology/Heredodegenerative Dystonia.")
Myoclonus-dystonia
Primary dystonias, particularly DYT1 dystonia, may be associated with
brief, myoclonic muscle jerks. However, researchers have described a
distinct genetic disorder in which dystonia may be associated with marked,
rapid, "lightening-like" myoclonus. Currently known as
"myoclonus-dystonia" or "inherited myoclonus-dystonia syndrome," the
disorder is characterized by variable combinations of dystonia and
myoclonus without other signs or symptoms of neurologic dysfunction (e.g.,
seizures, dementia, or impaired coordination of voluntary movements
[ataxia]). As mentioned earlier, myoclonus refers to sudden, involuntary,
"shock-like" muscle contractions, often accompanied by periodic
interruptions in voluntary muscle contraction (muscle inhibition). Many
researchers suggest that myoclonus-dystonia may represent the same
disease entity as so-called "hereditary essential myoclonus," a usually
familial disorder in which myoclonus is an isolated or primary finding
often occurring in association with dystonia.
In patients with myoclonus-dystonia, associated symptoms usually become
apparent during childhood or adolescence, although onset may occur during
adulthood. Myoclonus is often the most prominent feature, primarily
affecting muscles of the arms, shoulders, neck, and trunk and usually
sparing the face and legs. The myoclonic jerks typically occur or worsen
with voluntary movement (action myoclonus) and may be exacerbated by
stress or fatigue. In addition, in many patients, consumption of alcohol
may alleviate myoclonus; however, a "rebound" worsening of symptoms has
sometimes been described subsequent to alcohol intake.
In addition to myoclonus, some affected individuals may also develop
abnormal dystonic movements and postures. Myoclonic jerks and dystonic
spasms may affect the same muscle groups or occur independently of one
another. Various forms of dystonia have been reported in affected family
members, including upper limb, cranial, cervical, and trunk dystonia.
Rarely, dystonia may be the sole finding associated with the disorder.
The course of myoclonus-dystonia is usually relatively benign. In members
of some families, the dystonia or myoclonus may appear to spontaneously
subside (remission). However, in most patients, symptoms gradually
progress for a few years and then tend to stabilize with periodic
fluctuations or have mild spontaneous improvement.
Myoclonus-dystonia is transmitted as an autosomal dominant trait that
appears to have reduced penetrance and variable expressivity, with males
more commonly affected (in contrast to DRD). Genetic analysis of one
family with 8 affected members demonstrated mutations of the gene that
regulates production of the D2 dopamine receptor (DRD2) protein. The
genetic locus (designated DYT11) has been mapped to chromosome 11q23.
Further research is needed to determine whether all families with
myoclonus-dystonia (and the entity known as hereditary essential
myoclonus) are indeed affected by the same genetic disorder.
Heredodegenerative Dystonia
This etiologic classification refers to disorders in which
neurodegenerative changes may lead to dystonia as a primary feature and
other neurologic symptoms are typically apparent, particularly
parkinsonism. However, in some patients with these disorders, dystonia
may not develop and other neurologic features may be primary findings.
The term "heredodegenerative" is used since many of these disorders are
hereditary; however, it is important to note that some are of unknown cause.
The heredodegenerative dystonias include numerous disorders, such as
certain X-linked recessive, autosomal dominant, autosomal recessive,
and/or parkinsonism syndromes. Such disorders include the following:
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X-linked dystonia-parkinsonism (Lubag)
Huntington's disease
Wilson's disease
Neuroacanthocytosis
Rett syndrome
Parkinson's disease
Juvenile parkinsonism
Other heredodegenerative dystonias
X-linked Dystonia-parkinsonism
(Lubag)
Known as X-linked dystonia-parkinsonism or Lubag (which is its Filipino
name), this neurodegenerative disorder is transmitted as an X-linked
recessive trait. It has primarily been reported in young adult males from
the island of Panay in the Philippines. However, a few cases have been
described in which females who carry a copy of the disease gene
(heterozygous carriers) may manifest mild symptoms of the disorder, such
as relatively mild dystonia or chorea.
The mean age at onset is approximately 35 years, with 14 years the youngest
reported age at onset. Symptoms may initially include focal dystonia of
the neck; lower limbs; upper limbs; or trunk. Cranial involvement often
affects muscles of the jaw, mouth, lower face, and tongue
(oromandibular/lingual dystonia). In addition, in those with involvement
of the vocal cords, symptoms may include an unusual, high-pitched sound
upon inhalation (stridor). With disease progression, the dystonia usually
becomes generalized. In some patients, signs of parkinsonism may
accompany, precede, or "replace" symptoms of dystonia. Such findings may
include stiffness (rigidity), slowness of movement (bradykinesia), a
shuffling manner of walking (gait), and/or postural instability (although
resting tremor is rarely present). Less commonly, patients may develop
progressive parkinsonism as an isolated manifestation of the disorder.
The gene for X-linked dystonia-parkinsonism (DYT3) has been mapped to
chromosome Xq13.1. Neuroimaging studies may reveal neurodegenerative
changes (e.g., gliosis and neuronal loss) within substructures of the
basal ganglia (i.e., striatum). Parkinsonism symptoms may slightly
improve with L-dopa or dopamine agonist therapy, and dystonic features
may have only a partial response to anticholinergics or benzodiazepines,
such as clonazepam (Klonopin®). (For further information, please see the
section entitled "Treatment.")
Huntington's Disease
Huntington's disease (HD) is a genetic, progressive, neurodegenerative
disorder that usually becomes apparent during the fourth or fifth decades
of life. However, the age at onset is variable and ranges from early
childhood to late adulthood. HD is primarily characterized by the
development of emotional, behavioral, and psychiatric abnormalities;
loss of previously acquired intellectual or cognitive functioning; and
movement abnormalities (motor disturbances).
The classic signs of HD include the development of chorea—or involuntary,
rapid, irregular, jerky movements—as well as the gradual loss of thought
processing and acquired intellectual abilities (dementia). Dementia may
be associated with impairment of memory, abstract thinking, and judgment;
improper perceptions of time, place, or identity (disorientation);
increased agitation; and personality changes (personality
disintegration).
In patients with HD, the chorea may originally be limited to the fingers
or toes but may eventually extend to involve the arms, legs, face, and
trunk. As the disease advances, choreic movements tend to become
generalized and essentially blend or flow into one another, causing them
to appear relatively slow and writhing in nature (athetosis). Late in the
disease course, the involuntary movements may develop a dystonic quality
in which there may be unusual twisting motions and alternating or fixed
postures resulting from sustained muscle contractions. In addition,
dystonia may occur as a complication of therapy with dopamine receptor
blockers (antagonists). In patients who develop symptoms before age 20
(juvenile HD), motor disturbances may be characterized by muscle
stiffness and resistance to movement (rigidity), relative slowness of
movement (bradykinesia), tremors, and dystonia.
HD may be inherited as an autosomal dominant trait or, less commonly, occur
as the result of a new (sporadic) mutation of the disease gene. The
disorder results from abnormally long sequences or "repeats" of certain
basic chemical "building blocks" of DNA known as cytosine, adenine, and
guanine (i.e., unstable expanded CAG trinucleotide repeats) within the
disease gene's coded instructions. The disease gene, known as IT15, is
located on chromosome 4p16.3. The IT15 gene regulates or encodes
production of a protein known as huntingtin that is found in nerve cells
(neurons) throughout the brain. Progressive nervous system dysfunction
associated with HD results from loss of neurons in certain areas of the
brain, including the basal ganglia and cerebral cortex.
Wilson Disease
Wilson's disease is a genetic disorder of copper metabolism, leading to
an excessive accumulation of copper in certain tissues and organs,
including the liver, brain, kidneys, and/or corneas of the eyes. Without
prompt, appropriate treatment, the disorder may result in progressive
liver disease, degenerative changes of the brain, psychiatric
abnormalities, and other findings.
Generally, the younger the age at symptom onset, the greater the degree
of liver (hepatic) involvement. Associated findings may include
enlargement of the liver (hepatomegaly), acute or chronic liver
inflammation (hepatitis), scarring and impaired functioning of the liver
(cirrhosis), and other complications.
Neurologic signs of Wilson's disease appear to predominate in those with
symptom onset after age 20. Such neurologic signs typically become
apparent in the second or third decade of life, although they may appear
as late as the sixth decade. These findings may include dystonia; muscle
stiffness (rigidity); tremor; impaired coordination of certain voluntary
movements (ataxia); "swaying" of the head (head titubation); increasingly
impaired articulation of speech (dysarthria); and/or other findings.
Dystonia involving muscles of the face, tongue, and throat (pharynx) may
cause or contribute to dysarthria and may lead to additional findings,
such as an unusual whispering quality to the voice ("whispering"
dysphonia), drooling, and/or a fixed grinning expression (risus
sardonicus). In addition, dystonic movements and abnormal postures may
affect muscles of the arms, legs, and trunk. Some patients may also develop
cognitive changes, resulting in increasing irritability, anxiety, severe
depression, unusual behaviors, or other psychiatric problems. Additional
findings associated with Wilson's disease may include the presence of
distinctive, golden brown rings at the outer margins of the corneas
(Kayser-Fleischer rings); premature destruction of red blood cells,
leading to decreased levels of the oxygen-carrying component of the blood
(hemolytic anemia); and/or progressive kidney failure.
Wilson's disease is inherited as an autosomal recessive trait. The
disorder results from changes (mutations) in a gene, known as ATP7B,
located on chromosome 13 (13q14.3). The ATP7B gene regulates production
of a protein that plays a role in the transport of copper
(copper-transporting ATPase). Although the specific underlying defect in
Wilson's disease is unknown, some researchers suggest that it may be
related to the body's inability to produce sufficient levels of
ceruloplasmin, an enzyme in the fluid portion of the blood that binds to
copper and is involved in its transport and regulation. In patients with
neurologic signs of the disease, such findings are thought to result from
progressive involvement of certain regions of the basal ganglia.
Neuroacanthocytosis
Also known as choreoacanthocytosis, this neurodegenerative disorder is
usually inherited as an autosomal recessive trait. Symptoms typically
become apparent between the ages of 25 to 45 years. The disorder may be
characterized by dystonia; chorea; tics, including lip "smacking" and
"hissing" vocalizations; personality changes and cognitive decline;
seizures; parkinsonism; and/or atrophy of muscle tissue (amyotrophy) with
an abnormally high length-wise arch of the foot (pes cavus). The dystonia
may affect muscles of the face, mouth, and tongue and may often be provoked
by eating (i.e., action dystonia), leading to potentially mutilating lipand tongue-biting.
Neuroacanthocytosis is associated with atrophy and neuronal loss within
substructures of the basal ganglia, including the caudate nuclei and
putamen (collectively known as the striatum) and the globus pallidus.
There may also be neurodegenerative changes within the thalamus and
certain regions of the spinal cord (i.e., anterior horns). The disorder
may be confirmed by blood tests indicating that over 15 percent of red
blood cells are acanthocytes or abnormal circulating red blood cells that
have spur-like or thorny projections (i.e., acanthocytosis).
Rett Syndrome
Rett syndrome (RS) is a progressive neurodevelopmental disorder of
childhood onset that occurs almost exclusively in females. Infants and
children with RS usually appear to develop normally until about 6 to 18
months of age. They may then cease to acquire new skills and gradually
or suddenly lose previously obtained skills (developmental regression),
such as conscious control of the hands and the ability to vocalize most
sounds or words. Acquired hand and finger use is gradually replaced by
repetitive, distinctive, uncontrolled hand movements, such as hand
clapping, clenching, grasping and releasing, patting, mouthing, or
"washing" and wringing. In addition, the tongue may repeatedly twist or
contort in ineffective chewing movements, and there may be involuntary
grinding, gnashing, or clenching of the teeth (bruxism). Affected
children may also develop autistic-like behaviors; an impaired ability
to perform the motor movements required for coordinating walking (gait
apraxia) and trunk movements; breathing irregularities during waking
hours; seizures; feeding and swallowing difficulties; and growth
retardation. Over time, some patients may develop increasing motor
difficulties, whereas other associated symptoms may tend to stabilize or
improve over time. Increasing motor difficulties may include loss of the
ability to walk (although some may never have gained this ability);
increasing muscle weakness; spasticity; dystonia, most often involving
the legs; and/or other involuntary movements, such as myoclonus or
athetosis.
RS usually appears to occur randomly for unknown reasons (sporadically)
in the absence of a family history. Yet there have been some instances
in which the disorder has affected more than one family member,
particularly sisters or identical twins. In such cases, the disorder's
mode of inheritance remains uncertain, although some researchers suggest
that RS may be transmitted as an X-linked dominant trait or be due to
germline mosaicism in a parent.
In some females, RS is caused by mutations of a gene known as MECP2 on
chromosome X (Xq28) that is thought to be critical in brain development.
The protein regulated by this gene (methyl-CpG-binding protein 2 [MeCP2])
helps to control the expression of other genes or essentially "silence"
other genes at certain critical times in development. Some researchers
have speculated that RS may also result from mutations of DNA within
mitochondria (mtDNA)—i.e., the relatively small, rod-like structures
outside the nuclei of cells that serve as a major source of cellular energy.
Although the basic underlying defect in RS is unknown, defective
maturation of several neurotransmitter systems is thought to play some
role. Researchers have demonstrated reduced activity of several
neurotransmitters, including dopamine, norepinephrine, acetylcholine,
and serotonin, in certain regions of the basal ganglia and cerebral
cortex.
Parkinson's Disease
Parkinson's disease (PD) is a progressive neurodegenerative disorder with
a mean age of onset of approximately 55 years. Symptom onset before age
20 is known as juvenile parkinsonism (see below). PD is characterized by
slowness or poverty of movement (bradykinesia); muscle stiffness and
resistance to movement (rigidity); postural instability; and tremor
primarily while at rest. Additional characteristic findings may include
a shuffling, unbalanced manner of walking; forward bending or flexion of
the trunk; decreased blinking and a fixed or "mask-like" facial expression;
an unusually soft, weak voice; abnormally small, cramped handwriting
(micrographia); depression; or other symptoms and findings.
Dystonia may occur in association with untreated PD, such as
action-induced bending (flexion) of the foot that worsens with walking.
More specifically, there may be inward turning of the heel and upward
bending (flexion) of the sole of the foot (equinovarus deformity), with
flexion of the second to fifth toes and backward flexion (i.e., upward
bending or dorsiflexion) of the great toes. As mentioned earlier,
adult-onset lower limb dystonia suggests the possibility of PD or other
parkinsonism syndromes.
Many PD patients also may develop dystonic flexion of the trunk during
the disease course. Less commonly, untreated PD patients may be affected
by dystonia of the upper limbs. In addition, there have been a few reports
in which untreated individuals developed hemidystonia or focal dystonia
of muscles of the eyelids (blepharospasm); jaw, mouth, and lower face
(oromandibular dystonia); or neck (cervical dystonia). However, some
researchers have questioned the significance of such findings, indicating
that the frequency of focal dystonia in PD is similar to its expected
frequency in the same age group. As mentioned earlier, dystonia may also
develop as a complication of therapy for PD, occurring secondary to the
administration of L-dopa.
The specific cause of PD remains unknown. Ongoing research has focused
on the role that various genes, exposure to certain chemicals, and other
mechanisms may play in potentially causing the disorder. The symptoms and
findings associated with PD are thought to primarily result from
progressive loss of nerve cells within a certain region of the substantia
nigra and the striatum (nigrostriatal system) of the brain and associated
deficient production of the neurotransmitter
Juvenile Parkinsonism
Juvenile parkinsonism is a general term that refers to progressive
neurodegenerative disorders in which signs of parkinsonism develop before
approximately age 20. Juvenile parkinsonism may be primary and familial
or may occur secondary to other heredodegenerative disorders, such as
Huntington's disease.
Families have been reported in which primary juvenile parkinsonism
appears to be transmitted as an autosomal dominant or autosomal recessive
trait. Initial findings may include lower limb dystonia or signs of
parkinsonism, such as slowness of movement (bradykinesia), rigidity, and
tremor. Additional findings may include postural instability and balance
difficulties, mask-like facial expression, difficulties speaking
(dysarthria), and/or other features. As with PD, reports suggest that most
patients respond to therapy with L-dopa.
Other Heredodegenerative Dystonias
In addition to those described above, there are numerous additional
disorders that are classified as heredodegenerative dystonias. These
include...
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Other autosomal recessive disorders, such as ataxia-telangiectasia,
Hallervorden-Spatz disease, and homocystinuria
Certain mitochondrial disorders, such as Leigh disease
Other parkinsonism disorders, including progressive supranuclear
palsy (PSP) and cortical-basal degeneration (CBD)
Other Movement Disorders and
"Pseudodystonias"
Dystonia may also occur in association with other neurologic movement
disorders that are not normally classified as forms of dystonia. These
may include the following:
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Dystonic tics, which are often classified with other tic disorders
Paroxysmal dyskinesias (PD). These neurologic movement disorders
are characterized by abrupt, transient episodes of excessive or
disorganized (hyperkinetic or dyskinetic) movements, including any
combination of chorea; relatively slow, writhing motions that
appear to flow into one another (athetosis); dystonia; and/or
uncontrollable flinging movements of an arm, leg, or both
(ballismus). Various forms of PD have been described in which
paroxysmal episodes may...
o Be provoked by sudden voluntary movement or unexpected
stimuli (paroxysmal kinesigenic dyskinesia [PKD])
o Occur spontaneously or be triggered or exacerbated by
caffeine or alcohol consumption, stress, fatigue, or other
factors (paroxysmal non-kinesigenic dyskinesia [PNKD])
o Be precipitated by prolonged exertion (paroxysmal
exertion-induced dyskinesia [PED]) or sleep (paroxysmal
hypnogenic dyskinesia [PHD])
Pseudodystonias
There are also a number of disorders that have been described as
"pseudodystonias." Such disorders may be associated with sustained muscle
contractions, unusual twisting movements, and/or abnormal postures yet
are not typically considered true dystonias since they occur secondary
to reflex mechanisms or various other underlying abnormalities. Examples
include...
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Juvenile rheumatoid arthritis (JRA). JRA refers to a group of
inflammatory joint disorders of childhood onset resulting from
inflammation of the connective tissue membranes that line the
spaces between joints and bones (synovitis). These disorders are
characterized by inflammation, abnormal warmth, pain, and swelling
of one or more joints, potentially leading to stiffness, limitation
of movements, and fixed bending or extension of involved joints in
various positions or postures (contractures). Additional symptoms
and findings may also be apparent.
Seizures that may result in unusual, twisting, sustained postures
Arnold-Chiari malformation. This refers to developmental
abnormalities in which there is protrusion (herniation) of the
lower cerebellum and the lowest region of the brainstem through the
opening in the base of the skull (foramen magnum) into the upper
spinal canal (cervical vertebral canal). In some cases, there may
also be herniation of a region of the spinal cord and its surrounding
membrane through an opening in the spinal column (myelomeningocele).
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In some cases, associated symptoms may include certain findings
seen in various forms of dystonia, such as neck pain, rigidity,
and/or gait abnormalities.
Isaac's syndrome. This condition is characterized by progressive,
generalized muscle stiffness, twitching, spasms, and "rippling
waves" of muscle contraction due to excessive activity
(hyperexcitability) of the end regions of nerve fibers that supply
muscle fibers (motor neurons).
Stiff-man syndrome. This disorder, which typically becomes
apparent during middle age, is initially characterized by periodic
muscle stiffness and spasms. With disease progression that may
occur over months or years, spasms and stiffness gradually become
persistent in muscles of the limbs and trunk. In more advanced cases,
muscles of the face and those involved in swallowing and breathing
may become involved. Late in the disease course, painful spasms may
be precipitated by sudden noises, emotions, or attempted movement.
The muscle spasms may eventually lead to joint deformities.
Sandifer syndrome. This disorder of childhood is characterized by
periodic tilting of the head to the side in an apparent effort to
reduce stomach (gastric) contractions associated with
gastroesophageal reflux--or the backward flow of stomach contents
into the esophagus.
Klippel-Feil syndrome (KFS). KFS is characterized by abnormal
fusion of two or more bones of the spinal column in the neck
(cervical vertebrae). Associated findings may include an unusually
short neck, limited movements of the neck and head, and a low
hairline at the back of the head.
Genetic Designations for the
Dystonias
As mentioned throughout, several forms of dystonia have been given
specific "genetic designations" (genetic nomenclature). Following is a
summarized listing of such genetic dystonias and their designations:
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DYT1: This designation refers to the gene responsible for most cases
of early-onset and limb-onset primary dystonia. Also known as
Oppenheim dystonia, DYT1 dystonia is an autosomal dominant disorder
with reduced penetrance and variable expressivity. The DYT1 gene,
which has been mapped to chromosome 9q34.1, regulates production
of the torsinA protein. DYT1 dystonia is most common among
individuals of European Ashkenazi Jewish descent. (For further
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information, please see the section entitled "Etiology/Primary
Dystonia.")
DYT2: This genetic designation was reserved for a possible
autosomal recessive primary dystonia. However, no such form has yet
been confirmed.
DYT3: This refers to the gene for a neurodegenerative, X-linked
recessive disorder that may be characterized by dystonia and
parkinsonism. Known as X-linked dystonia-parkinsonism or Lubag,
the disorder has been reported primarily in young adult Filipino
men. The DYT3 gene has been mapped to chromosome Xq13.1. (For
further information, please see the section entitled "
Heredodegenerative dystonia.")
DYT4: This genetic designation is for an autosomal dominant primary
dystonia in a multigenerational Australian family. DYT4 dystonia
is primarily characterized by abductor ("whispering") spasmodic
dysphonia (laryngeal dystonia).
DYT5: This refers to the gene known as GTP cyclohydrolase I (GCH1),
which has been mapped to chromosome 14q22.1. Mutations of the GCHI
gene may result in the dystonia-plus syndrome called
dopa-responsive dystonia (Segawa syndrome), which is transmitted
as an autosomal dominant trait. (For further information, please
see the section entitled "Dystonia-plus syndromes.")
DYT6: This is for an autosomal dominant primary dystonia mapped to
chromosome 8 (8p21q22). Described in 2 Mennonite families
(kindreds), this form of dystonia may be of childhood- or
adult-onset; initially affects limb, cranial, or neck muscles; and
typically extends to involve multiple body regions. (For further
information, please see the section entitled "Etiology/Primary
Dystonia.")
DYT7: This genetic designation is for an autosomal dominant,
adult-onset, primary dystonia of the neck region (familial
torticollis) that has been mapped to chromosome 18p in a German
kindred. (For further information, please see the section entitled
"Etiology/Primary Dystonia.")
DYT8: This designation is for a neurologic movement disorder known
as paroxysmal non-kinesigenic dyskinesia (PNKD) that may be
inherited as an autosomal dominant trait. PNKD is characterized by
sudden, transient episodes of excessive or disorganized
(hyperkinetic or dyskinetic) movements that may occur
spontaneously or be triggered or worsened by stress, fatigue, or
other factors. Abnormal movements may include any combination of
dystonia, chorea, athetosis, and/or ballismus. DYT8 has been mapped
to chromosome 2q33-q35. (For further information, please see the
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section entitled "Other movement disorders and
'pseudodystonias.'")
DYT9: This genetic designation is for a family affected by an
autosomal dominant disorder known as "choreoathetosis spasticity,
episodic" or CSE. It is characterized by sudden, transient
(paroxysmal) attacks of dyskinesia—such as chorea, athetosis,
limb dystonia, imbalance, and difficulties speaking
(dysarthria)—that, in some cases, may be associated with constant
weakness and stiffness of the legs (spastic paraplegia). Paroxysmal
episodes may be precipitated by physical exercise, lack of sleep,
alcohol consumption, stress, or other factors. DYT9 has been mapped
to chromosome 1p.
DYT10: This designation is for paroxysmal kinesigenic dyskinesia
(PKD), a neurologic movement disorder that may be transmitted as
an autosomal dominant trait. In patients with PKD, sudden episodes
of dyskinesia, including dystonic movements, may be triggered by
sudden voluntary movement or unexpected stimuli (startle). DYT10
has been mapped to chromosome 16p11.2-q12.1. (For further
information, please see the section entitled "Other movement
disorders and 'pseudodystonias.'")
DYT11: This refers to an autosomal dominant disorder known as
myoclonus-dystonia resulting from mutations of a gene that
regulates production of the D2 dopamine receptor (DRD2) protein.
Genetic analysis of a family with 8 affected members demonstrated
mutations of the DRD2 gene, which has been mapped to chromosome
11q23. Evidence suggests that this may be the same disorder as
hereditary essential myoclonus. (For further information, please
see the section entitled "Dystonia-plus syndromes.")
DYT12: This designation is for the gene responsible for rapid-onset
dystonia-parkinsonism (RDP), an autosomal dominant disorder. The
DYT12 gene has been mapped to chromosome 19q. (For further
information, please see the section entitled "Dystonia-plus
syndromes.")
As mentioned earlier, investigators expect that additional genetic forms
of dystonia—particularly familial primary dystonias—will be identified
that may be provided with genetic designations in the future (e.g., DYT13,
etc.). In addition, some experts indicate that traditional
classifications of dystonia (i.e., clinical and etiologic
classifications) may gradually be revised or replaced by genetic
classifications as more is learned about the specific underlying genetic
mechanisms of dystonia.
Epidemiology
Due to the variability of associated symptoms and disease severity and
the fact that some patients with mild cases may remain undiagnosed, it
is difficult to determine the specific frequency of primary dystonia in
the general population. However, according to a 1998 study conducted in
Rochester, Minnesota, the frequency was estimated to be 29.5 individuals
per 100,000 for focal dystonias and 3.4 per 100,000 for generalized
dystonias. As mentioned earlier, early-onset primary dystonia is most
common among individuals of European Ashkenazi Jewish descent. It has been
estimated that the frequency is approximately 0.5 to 4 individuals per
100,000 in the non-Jewish population, with some experts suggesting that
individuals of Ashkenazi Jewish ancestry may be affected about 3 to 5 times
as frequently. However, a recent investigation has reported an even higher
frequency of approximately 20 to 30 individuals per 100,000 in the
Ashkenazi Jewish population. Evidence indicates that the late-onset
primary dystonias do not appear to have a higher frequency among those
of Ashkenazi Jewish descent as compared with the non-Jewish population.
There are few epidemiological studies on dystonia and its various forms.
A large European study, reported in the literature in 2000, estimated the
crude annual period prevalence rate for primary dystonia (for 1996-1997)
at 152 per million. Of the primary dystonias, focal dystonia had the
highest relative rate at 117 per million. The prevalence rates for the
other dystonias were estimated as follows: 57 per million for cervical
dystonia; 36 per million for blepharospasm; and 14 per million for
writer's cramp. The relative rates, adjusted for age, were substantially
higher in women than in men for the segmental and focal dystonias. The
exception to this was writer's cramp. The authors (Warner T et al.) point
out that these estimates should be viewed as "under-estimates" of the true
prevalence of dystonia. Their estimates are seen as conservative due, in
part, to under-ascertainment of cases.
Pathophysiology
No consistent or specific changes in brain tissue or function have been
seen in individuals with primary dystonias, and the basic underlying
defect or defects in these disorders remain unknown. However,
investigators suggest that the primary dystonias as well as dystonia-plus
syndromes probably result from abnormalities in the activity of chemicals
in the brain known as neurotransmitters, such as an imbalance of dopamine
transmission, within the basal ganglia. (As mentioned earlier,
neurotransmitters are naturally produced chemicals that may transfer
nerve impulses across the spaces between neurons, enabling nerve cells
to communicate. The basal ganglia consist of specialized nerve cell
clusters deep within the brain that organize motor behavior.) Thus, these
disorders may be considered neurochemical in origin—i.e., neurochemical
disorders that do not appear to result in structural neurodegenerative
changes. (In contrast, heredodegenerative disorders are usually
hereditary disorders in which structural neuronal degeneration may be
associated with neurochemical abnormalities.) An underlying
neurochemical basis for many dystonias may be suggested by multiple
factors, including evidence that secondary dystonia may result from
treatment with the dopamine precursor L-dopa (such as used for treatment
of Parkinson's disease) or therapy with dopamine receptor blockers
(antagonists). As mentioned earlier, the dystonia-plus syndromes also are
nondegenerative, neurochemical disorders that are distinguished from
primary dystonias due to the presence of neurologic features in addition
to dystonia (e.g., myoclonus or parkinsonism). Specifically,
dopa-responsive dystonia (DRD) and several DRD variants have been shown
to result from reduced production of dopamine and/or other
neurotransmitters in the basal ganglia.
Abnormalities in the activities of certain neurotransmitters have also
been demonstrated in heredodegenerative disorders (e.g., Parkinson's
disease, Rett syndrome, etc.). In addition, anatomic studies of focal
brain lesions associated with certain secondary dystonias and specific
neurodegenerative changes found in heredodegenerative dystonias (e.g.,
Wilson's disease, Huntington's disease, neuroacanthocytosis, etc.)
implicate dysfunction of the basal ganglia and its connections (e.g.,
thalamus, cerebral cortex, or, rarely, the brainstem) as a cause of such
dystonias--and further support the theory that primary dystonias may
result from abnormalities of the basal ganglia.
Electrophysiology
Electromyography (EMG) is a diagnostic test in which the electrical
activity of voluntary (skeletal) muscles are measured at rest and during
voluntary action. In patients with dystonia, EMG may reveal little or no
activity at rest or prolonged bursts of electrical activity with overflow
to muscles that are not normally involved. More specifically, abnormal
EMG patterns at rest may include any of the following:
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Relatively long spasms that result in abnormal, sustained postures
Repetitive bursts of electrical activity that are of "mid range"
in length (i.e., approximately 200 to 500 milliseconds). (Note: EMG

bursts usually do not last longer than approximately 100
milliseconds.)
Irregular bursts or jerks that are short (i.e., less than 100 ms),
resembling those associated with myoclonus.
In addition, any of the above EMG patterns may also occur with voluntary
movements. Patients with dystonia usually have difficulty selectively
initiating movement of appropriate muscles required for certain voluntary
actions and experience simultaneous contraction of antagonist muscles.
In addition, there is a decrease in or loss of the active inhibition of
antagonist muscles that normally occurs with voluntary contraction of
agonist muscles. Some researchers suggest that this finding—i.e.,
decreased inhibition leading to an "overflow" of movement—may result
from loss of inhibition at the level of the cerebral cortex, brainstem,
and spinal cord via the basal ganglia and its pathways. (The basal ganglia
cells of origin of the inhibitory pathways are under the control of the
activities of the neurotransmitter dopamine.) Such a theory may
potentially explain how dystonia may result from or be triggered by
different mechanisms. For example, according to such a theory,
significant loss of inhibition potentially leading to dystonia may result
from lesions of certain areas of the brain; specific genetic abnormalities;
or a genetic predisposition that may be triggered by environmental factors,
such as abnormal sensory input resulting from repeated use and/or trauma
of the affected body part.
Concerning sensory input, there is some evidence suggesting that certain
abnormalities in the brain's ability to process sensory information may
also play some role in causing dystonia by altering brain motor control.
According to researchers, this possibility is supported by various
factors, including the "sensory tricks" seen in many patients with
dystonia and the fact that some patients may develop certain sensory
symptoms prior to the development of dystonia. For example, such sensory
symptoms have included a gritty feeling in the eye and increased
sensitivity to light (photophobia) prior to onset of blepharospasm. In
addition, repeated use or peripheral trauma of a body part may result in
abnormal sensory input, potentially triggering the onset of dystonia.
Further research is needed to learn more about the potential causative
role of loss of inhibition, sensory dysfunction, peripheral trauma,
and/or other mechanisms in dystonia.
Diagnosis
The diagnostic evaluation of dystonia may include the following:


General physical and neurologic examinations
Evaluation of the nature of the dystonia, including...
o Apparent age at symptom onset
o Bodily distribution
o Disease progression
o Whether dystonia occurs with specific actions
o If it is characterized by "overflow"
o If it is present at rest
o Whether certain "sensory tricks" temporarily suppress
dystonic movements
For example, the presence of hemidystonia—or rest dystonia rather than
action dystonia at symptom onset—is strongly suggestive of secondary
dystonia. Identification of certain features may suggest that symptoms
have an emotional rather than an organic origin [psychogenic disease],
such as abrupt onset, changing characteristics over time, spontaneous
remissions, etc. And early limb-onset dystonia in the absence of other
findings may suggest primary dystonia possibly due to DYT1 gene mutation
[Oppenheim dystonia].) During clinical evaluation to assess the nature
of the dystonia, patients may be examined and videotaped while performing
various actions, such as sitting, standing, lying down, or walking.
In addition, if the dystonia is not always present, the examiner may use
various methods to help "trigger" dystonic spasms to aid in diagnosis,
such as requesting that a patient with suspected blepharospasm repeatedly
open and shut his or her eyes. The examiner may also conduct passive
movements of the affected bodily region, carefully feel (palpate)
contracting muscles, and/or request that a patient adapt various
positions or postures with the affected area. Such methods may be
necessary for accurate diagnosis, appropriate assessment of the nature
of dystonia, and localization of involved muscles (e.g., for those who
may be appropriate candidates for therapy with botulinum toxin). Such
evaluation may be documented by videotaped recordings. For those patients
with suspected laryngeal dystonia, voice assessment is typically
documented on voice recordings.
Additional evaluations may include assessment by a speech-language
pathologists, when appropriate, physical or occupational therapists, or
genetic counselors.

A thorough patient history to help determine or exclude causative
factors potentially associated with secondary dystonia, such as
exposure to certain medications, particularly dopamine antagonists;
exposure to certain toxins; peripheral, head, or spinal trauma;
certain infections or inflammatory conditions of the brain; etc.
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A careful family history
Laboratory studies, such as blood and urine tests, analysis of
cerebrospinal fluid (CSF), and/or other studies. Blood tests may
include erythrocyte sedimentation rate (ESR), antinuclear
antibodies (ANA) studies, tests to detect the presence of
acanthocytes or abnormal red blood cells that have spur-like
projections (i.e., a finding that may be suggestive of
neuroacanthocytosis), and/or other studies. (ESR measures the rate
at which red blood cells settle in a tube of unclotted blood,
potentially serving as a nonspecific indicator of inflammation.
ANAs, which are antibodies that act against certain of the body's
own cells [autoantibodies], are commonly seen in patients with
certain autoimmune disorders.) If diagnosing physicians suspect
certain heredodegenerative dystonias due to specific metabolic
defects, laboratory studies may also be conducted to detect the
levels of certain enzymes (e.g., lysosomal enzymes, etc.). In
addition, particularly for children, adolescents, and adults
younger than approximately age 40, studies may be recommended to
measure levels of the enzyme ceruloplasmin in the fluid portion of
the blood (serum). Abnormally low ceruloplasmin serum levels may
suggest a diagnosis of Wilson's disease. For some patients, other
laboratory studies may also be appropriate.
Electrical recording techniques, such as electromyography (EMG);
nerve conduction velocity tests; or other methods (e.g., reflex
studies). In addition, in some instances, diagnostic evaluation may
include electroretinography, which measures the retina's
electrical response to light stimulation; electroencephalography
(EEG) to detect or rule out potential seizure activity (such as in
some individuals with paroxysmal dyskinesias); or other
techniques.
Biopsies. In selected patients, diagnostic assessment may include
surgical removal and microscopic evaluation (biopsy) of small
samples of skin, muscle, and/or nerve tissue.
Ophthalmologic examination, including examination of internal
structures at the front of the eyes with an illuminated microscope
(slit lamp examination). Such examination may be recommended for
children, adolescents, and adults under approximately age 40 to
help confirm or rule out the presence of Kayser-Fleischer rings.
As mentioned earlier, these are gold-like, brownishrings around the
corneas of the eyes that are present in many patients with Wilson
disease. They are typically present in patients who manifest
neurologic and psychiatric abnormalities associated with this
heredodegenerative disease.
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
Thorough neurologic evaluations to help confirm or exclude the
presence of other neurologic signs that may suggest secondary
dystonias, dystonia-plus syndromes, or heredodegenerative
disorders. Such neurologic signs may include certain eye (ocular)
abnormalities (e.g., optic atrophy, retinal abnormalities);
parkinsonism; myoclonus; impaired coordination of voluntary
movements (ataxia); spasticity; muscle weakness; dementia;
seizures; and/or other findings.
Neuroimaging studies, such as computerized tomography (CT)
scanning or magnetic resonance imaging (MRI), to create detailed,
cross-sectional images of the brain and spinal cord. Such studies
may be recommended for those in whom patient history and clinical
examination suggest the possibility of structural lesions that may
be responsible for secondary or heredodegenerative dystonias.
According to experts, individuals with early-onset apparently isolated
dystonia should undergo specific tests to help exclude Wilson disease
(e.g., slit lamp examination, serum ceruloplasmin). If patient and family
history and physical examination reveal certain symptoms, signs, and
physical findings suggestive of secondary or heredodegenerative
dystonias, more extensive diagnostic testing may be recommended, such as
enzymatic studies (assays), neuroimaging studies, etc. For those with
primary dystonias, dystonia is typically the only sign upon examination
(i.e., with the possible exception of tremor or brief myoclonic jerks).
In such cases, most diagnostic studies may not provide any revealing
findings.
However, for individuals with early-onset or limb-onset dystonia,
regardless of their family history or ancestry (i.e., whether of Ashkenazi
Jewish or non-Jewish descent), DNA testing is now available to help
confirm or exclude primary dystonia due to mutation of the DYT1 gene.
During such testing, blood samples are taken from patients and DNA is
directly analyzed for the presence of the GAG (guanine, adenine, guanine)
deletion in the DYT1 gene's coded instructions. In addition to confirming
or ruling out DYT1 dystonia in patients with symptoms, such testing may
also help to detect or exclude the DYT1 gene mutation in family members
of diagnosed individuals and may be conducted prenatally. As mentioned
earlier, however, evidence indicates that only 30 to 40 percent of those
who carry a mutated DYT1 gene for the disease manifest symptoms (reduced
penetrance). Therefore, a majority of those with the mutated gene do not
develop the disorder. There currently is no way to predict whether an
individual with the disease gene will develop dystonia. Because the
disorder has reduced penetrance as well as variable expressivity among
those who do develop symptoms, experts recommend that genetic counseling
should be provided for individuals who are considering diagnostic,
carrier, or prenatal DYT1 DNA testing.
For patients with early-onset generalized or segmental limb dystonia who
test negative for the DYT1 gene mutation, physicians may recommend a
diagnostic trial with the agent levodopa (L-dopa). The dystonia-plus
syndrome known as dopamine-responsive dystonia (DRD) is suggested in
young patients with dystonia who have significant improvement with
low-dose L-dopa therapy. In contrast, most dystonia patients who do not
have DRD do not have a response to treatment with L-dopa or dopamine
agonists. Thus, if no improvement is noted after approximately 3 months
of L-dopa therapy, a diagnosis of DRD is considered unlikely and such
treatment may be stopped.
For some patients with adult-onset focal dystonias that are presumed to
be primary—e.g., based upon thorough clinical examination, a complete
patient and family history, nature of the dystonia, absence of certain
signs upon examination, etc.—experts indicate that extensive laboratory
or neuroimaging studies may not be necessary. As discussed above, if
patients are under 40 years of age, they should receive specific tests
to help exclude Wilson disease. In addition, the presence of certain
unusual (atypical) signs may suggest the need for additional testing. For
example, as mentioned previously, adult-onset lower limb dystonia is
extremely rare; therefore, such patients should receive diagnostic
evaluations to determine whether the condition has occurred secondary to
Parkinson's disease or other parkinsonism syndromes. However,
individuals with typical adult-onset focal dystonias, particularly those
who have been affected for several months or more, may not require further
diagnostic evaluations unless new signs or unusual symptoms develop.
It is possible that DNA analysis may assist in diagnosing other forms of
dystonia caused by known mutations of specific genes in certain families.
However, such testing may be considered investigational and/or may not
be widely available. As more is learned about the genetic causes of the
different forms of dystonia, it is hoped that such information will lead
to additional laboratory studies and greater availability of such testing
to help confirm the diagnoses.
Approaches to Treatment
The first step in treatment is attempting to determine the cause of the
dystonia. For secondary dystonias, treating the underlying cause may
improve the dystonia. For instance, treatments for neurological
conditions such as multiple sclerosis or Parkinson's disease may reduce
dystonic symptoms. Withdrawing or reducing neuroleptic drugs leads to
slow improvement in some cases.
There are three main approaches to the treatment of dystonia: oral
medications, injections of therapeutic agents directly into dystonic
muscle, and surgery. Physical therapy may play a role for some patients,
most often as a supplement to other therapies such as botulinum toxin.
Supportive therapy provides an important adjunct to medical treatment for
many patients. There are currently no known treatments that can reverse
the course of primary dystonia. However, symptoms may usually be managed
well with a combination of treatments.
For example, patients with dopa-responsive dystonia (DRD) improve
significantly with small doses of levodopa. Neurologists often try a
course of levodopa therapy for patients with limb-onset dystonia in order
to determine if DRD is the cause. Most patients who do not have DRD will
not have a strong response to levodopa or to other dopaminergic drugs,
such as dopamine agonists.
Support and advocacy organizations are important resources for
individuals with dystonia and their families. Newsletters, group meetings,
and Internet-based discussion groups offer opportunities for sharing of
information, exchanging psychological support, and becoming involved in
promoting research on dystonia and its treatments. A full list of
international support and advocacy groups is available here.
Pharmacologic Treatment of Dystonia
There are a number of treatment options available to treat dystonia. Drugs
may be used alone or in combination. In addition, they may be combined
with other forms of treatment.
Botulinum toxin (BTX)
Botulinum toxin (BTX) is a biological therapeutic agent that acts against
dystonia. Botulinum toxin is a toxic protein that is produced by the
bacterium Clostridium botulinum. The use of botulinum toxin (BTX)
represents a significant advance in the treatment of dystonia. This toxin
is known to cause botulism, a deadly form of food poisoning that is
contracted through the ingestion of contaminated food products. However,
when a minute amount of commercially prepared BTX is injected directly
into an overactive muscle, it relaxes the muscle.
BTX blocks the release of acetylcholine, a neurotransmitter responsible
for activation of muscle contraction. Thus, BTX decreases inappropriate
or excessive muscle contractions, allowing the affected area (e.g., arm,
neck, leg, eyelid, etc.) to assume a more normal position or posture.
There are seven forms (serotypes) of botulinum toxin; namely, types A,
B, C, D, E, F, and G. Each serotype of has a distinct structure and
mechanism of action. In the United States, only two BTX products have been
approved by the U.S. Food and Drug Administration (FDA). They are BOTOX®
(a BTX-A product produced by Allergan, Inc.) and Myobloc™ (a BTX-B product
produced by Solstice Neurosciences). Another BTX-A product–Dysport®
(Ipsen, Ltd.)–is available, but has not been approved by the FDA for use
in the United States. Each BTX product is unique, with its own safety,
efficacy, and immunogenicity profile.
Botulinum Toxin Type A for Dystonia
Injections of botulinum toxin type A have been used in the management of
dystonia since the late 1980s. BOTOX® (Allergan, Inc.) was approved in
the United States by the FDA in 1989 for use in patients ages 12 and above
who were affected by strabismus, blepharospasm associated with dystonia,
including benign essential blepharospasm–or disorders of the seventh
cranial nerve. Since then, BTX-A has been used widely in the management
of focal dystonia, as well as other disorders characterized by excessive
muscle spasms.
On December 27, 2000, the FDA approved the use of BOTOX® for the treatment
of cervical dystonia (CD). Injections of this product decrease the
severity of abnormal head positioning and postures as well as associated
neck pain. Another botulinum toxin type A product, Dysport®, is produced
and distributed by Ipsen, Ltd., but has not been approved for use within
the United States. The appropriateness of BTX-A or of any dystonia
therapy–relies on its ability to meet the goals of patients and
caregivers as outlined in their comprehensive treatment plan.
Administration of BTX-A for the treatment of dystonia
A solution of BTX-A is injected directly into several sites in the
overactive, dystonic muscle. These sites are near the nerve terminals or
that part of the nerve cell that actually stimulates the muscle to contract.
BTX-A works inside the nerve terminals to block the release of the
neurotransmitter acetylcholine. This neurotransmitter serves to initiate
or elicit muscle contractions. Some nerve terminals remain unaffected by
BTX-A; therefore, the injected muscle may still contract but with less
force. One important benefit of BTX-A is that the dose may be adjusted
to provide the precise degree of weakness needed to overcome dystonia;
however, some strength for normal function is preserved.
BTX-A temporarily weakens dystonic muscles, thereby allowing for a more
normal posture and function. The benefits that BTX-A conveys to a
particular patient depend on the location and relative degree of severity
of the dystonic muscles being injected. In general, BTX-A cannot be used
alone to treat widespread or extremely severe generalized dystonia, as
the drug dose required for this type of treatment would be too high. In
these patients, BTX-A may be used to target specific dystonic muscles,
thereby improving particular aspects of care and function or relieving
discomfort or pain. Many patients with painful muscle spasms report a
reduction in pain after injection with BTX-A.
Duration of BTX-A effects
The effects of treatment with BTX-A are usually greatest for a two- to
six- week period following injection. In most patients treated with BTX-A
(BOTOX® or Dysport®) these treatment effects typically fade approximately
three to six months after injection administration. If necessary,
reinjection of the drug is possible at that time. In order to decrease
the possibility of antibody formation, reinjections are not administered
before three months after the last injection.
Side effects of BTX-A
During the dose regulation process, physicians work closely with patients
to optimize their therapy. Some patients may experience temporary, muscle
weakness. This weakness is temporary and wears off. If patients experience
muscle weakness, it is important to discuss this finding with their
physicians as it may be a signal for a modification of the treatment
approach. For example, muscle weakness may be lessened by reducing the
dose of BTX-A during the next injection. BTX-A should be used with extreme
caution in patients with neuromuscular disease such as myasthenia gravis
or amyotrophic lateral sclerosis (ALS or motor neuron disease), or in
those who receive therapy with drugs that thin the blood (anticoagulants),
or certain antibiotics (aminoglycosides such as gentamicin [Garamycin®],
kanamycin [Kantrex®], neomycin [Mycifradin®, Myciguent®, or NeoTab®],
streptomycin [Streptomycin], or tobramycin [Tobrex® or Nebcin®]).
The decision to combine injections of BTX-A with other forms of treatment
for dystonia is an individual decision and based on many factors. This
decision is reached after thorough clinical evaluation and consultation
with the treating physician. In some patients receiving injections of
BTX-A, the dosage of other medications may be reduced. Certain oral
medications as well as baclofen, which may be delivered directly next to
the spinal column (intrathecally), may provide global muscle tone
reduction, whereas BTX-A injections may provide graded focal relief in
selected muscles.
Injection of BTX-A
During the administration of BTX-A, a relatively small needle is placed
into the target muscle. In large or accessible muscles, confirmation of
appropriate placement of the injection into the target muscle may be
achieved by feeling the muscle. In small or deep muscle groups,
electromyography (EMG) or electrical stimulation may be required to
confirm appropriate placement.
Small muscles may be injected in only one or two sites. Larger muscles
may require three to four injection sites. Most individuals are able to
tolerate these small needle punctures; however, if necessary, local
anesthetic cream or sedation may help ease discomfort or anxiety
associated with injection. This may be particularly useful for children
who are receiving injections.
Antibodies and BTX therapy
Antibodies are proteins produced by the immune system to help fight
infections or dispose of other foreign agents that enter the body. In some
individuals treated with BTX-A, antibodies may develop, bind to the drug,
and inactivate it. This renders BTX ineffective in weakening muscle
contractions associated with dystonia. It is estimated that approximately
five percent of individuals with cervical dystonia who have been treated
regularly with relatively higher doses of BTX-A develop antibodies. Once
a patient forms antibodies to a particular serotype of BTX
(immunoresistance), further injections of that particular serotype of BTX
are typically ineffective. Physicians should, therefore, use the smallest
amount of BTX-A necessary to achieve therapeutic benefit; extend the time
interval between treatment sessions as long as possible (with at least
three months between treatments); and, if possible, avoid the use of
"booster" injections. A new, lower protein form of BOTOX® is available.
It is theorized that lower protein may lead to lower rates of antibody
formation (reduced immunogenicity). See E-MOVE Article: BTX-A current
bulk toxin vs. original (AAN report).
On occasion, a patient may not respond to therapy with BTX-A. So-called
"primary non-responders" are patients who do not respond to their first
injection of BTX. Secondary non-response may occur as the result of a
technical problem, such as an inappropriate site of injection into the
wrong muscle, a dose that is inadequate to provide a clinical effect, or
disease progression. The toxin may weaken the muscle; however, the degree
of relaxation may not provide symptomatic relief for the patient. In
addition, some patients on combination therapies for segmental or
generalized dystonias may fail to take their oral medications, leading
to a general increase in symptoms (masking the local effects of BTX-A).
If failure to respond continues, it is possible that the patient has
antibody-mediated resistance (immunoresistance).
It is important that patients work with their physicians to set
appropriate treatment goals and tailor the course of treatment to meet
these goals. There is no formal "recipe" that works for every patient.
Each individual is unique and responds differently to BTX-A therapy.
Botulinum Toxin Type B for Dystonia
On December 11, 2000, a botulinum toxin type B product (Myobloc™) was
approved by the FDA in the United States as a treatment for patients with
cervical dystonia. Myobloc™ is the U.S. trade name for Solstice
Neurosciences' botulinum toxin type B product. This product also received
marketing authorization from the European Union's Committee for
Proprietary Medicinal Products and is available there as Neurobloc®.
Safety and efficacy were demonstrated in double-blind clinical trials in
patients who had responded to BTX-A and in patients who had developed
resistance to BTX-A. BTX-A and BTX-B have slightly different chemical
structures and their primary mechanisms of action on acetylcholine also
differ.
Please refer to E-MOVE Article: BTX-B for cervical dystonia (AAN report)
Please see: Toxins '99 Meeting Reports
Other Medications Used to Treat
Dystonia
Benzodiazepines
Benzodiazepines are a class of drugs that interfere with chemical
activities in the nervous system and brain, serving to reduce
communication between nerve cells. Consequently, such medications may
relax muscles and ease symptoms associated with dystonia. Benzodiazepines
are oral medications that may be used to treat focal, segmental, and
generalized dystonias. Diazepam (Valium®) and clonazepam (Klonopin®) are
two types of benzodiazepines that are most commonly used to treat dystonia.
The major side effect of these drugs is drowsiness, which may be controlled
by lowering the dose. At relatively high doses, side effects may include
depression, personality changes, or, in severe cases, psychosis.
Baclofen
Baclofen (Lioresal®) is a drug that is used to treat individuals with
spasticity. In addition, this drug has been administered to some patients
with dystonia. Baclofen's primary site of action is the spinal cord where
it reduces the release of neurotransmitters that stimulate muscle
activity (GABA agonist stimulating GABAB autoreceptor). Baclofen has been
used to treat both primary and secondary dystonias. This drug may be
administered orally or via a surgically implanted pump that delivers the
drug directly to the spinal cord (intrathecal baclofen).
Anticholinergics
Anticholinergic drugs block the action of the neurotransmitter
acetylcholine, thereby deactivating muscle contractions. These drugs are
administered orally and used to treat focal, segmental, and generalized
dystonias. Trihexyphenidyl (Artane®) and diphenhydramine (Benadryl®) are
the most common anticholinergic agents used to treat dystonia. This form
of therapy may be more beneficial in children, as they are frequently able
to tolerate higher doses of trihexphenidyl than adults. Greater
therapeutic benefits may also occur in those patients who initiate drug
therapy early during the course of their disease. Side effects may be
severe, particularly at higher doses. These may include confusion,
drowsiness, hallucinations, forgetfulness, personality changes, dry
mouth, blurred vision, and urinary retention.
Dopamine-blocking agents/Dopamine-depleting agents
Dopamine-blocking or dopamine-depleting agents may be used to treat some
patients with dystonia. The possible positive effect of these agents is
a paradox since dopamine blockers may also cause dystonia. Nonetheless,
these agents have been shown to be effective in some patients. Although
not available in the United States, tetrabenazine is the most widely used
dopamine-blocking agent. In some patients, tetrabenazine may be combined
with lithium, which may help to lessen side effects such as slowed
movements and depression. Other dopamine blockers are not as commonly used,
since they may be more likely to evoke tardive dystonia. The neuroleptic
drugs clozapine and olanzapine may be useful for the treatment of dystonia
and may be less likely to cause tardive dystonia. See E-MOVE Article:
Cervical dystonia: mixed results for clozapine.
Surgical Treatment of Dystonia
Thalamotomy and Pallidotomy
Surgical intervention may be considered in those patients with severe
dystonia who have not responded or become non-responders to drug therapy.
Thalamotomy and pallidotomy, which are surgeries used to treat
individuals with Parkinson's disease, are now used to treat those with
dystonia. During these two forms of surgery, specific areas deep within
the brain that are involved with the initiation and generation of movement
are targeted for destruction.
During a stereotaxic thalamotomy, a selected portion of the thalamus is
surgically destroyed (ablated). The thalamus is a paired structure deep
within the brain that is involved in the control of movement. In this
procedure, neurosurgeons use specialized equipment, enabling them to use
three-dimensional coordinates to precisely locate an area of the thalamus.
Extreme care is exercised this structure is deep within the brain and
located near other important structures. The possible complications of
thalamotomy include contralateral weakness (hemiparesis), confusion, or
dysarthria. Although these symptoms are relatively common during the
postoperative period, they are usually short-lived and recede within a
short period.
A pallidotomy involves destruction of part of the globus pallidus (GPi),
a region of the brain involved with the control of movement. Destroying
part of the GPi may help to restore the balance that normal movement
requires. Pallidotomy is performed by insertion of a wire probe into the
GPi. Once its placement has been confirmed by electrical tests, the probe
heats surrounding tissue by emission of radio waves. The heat destroys
nearby tissue. This procedure does involve risk and complications occur
in about 10 percent of patients. For example, the surgical probe may strike
a blood vessel during insertion, causing a slight stroke. Damage to
non-target brain areas is also possible.
The goal of surgery for individuals with dystonia is to attempt to
"rebalance" movement and posture control by destroying one or the other
of these regions deep within the brain. These procedures have been
performed in relatively few patients with dystonia as compared to their
widespread use in those with Parkinson's disease. However, studies have
shown these surgeries to be effective in most patients. Adverse effects
may be considerable and include swallowing and speech difficulties as well
as bleeding into the brain (cerebral hemorrhage).
Deep Brain Stimulation
Deep Brain Stimulation (DBS) is an invasive surgical procedure that seems
to mimic the positive effects of surgical ablation performed during a
thalamotomy or pallidotomy. During this procedure, electrodes are
implanted in a specific area of the brain (i.e., thalamus or, more recently,
globus pallidus). In addition, a device known as an implantable pulse
generator (IPG) is placed under the skin in the area of the collarbone.
After appropriate postoperative testing, leads from the implanted
electrodes are connected to the pulse generator, which then delivers
continuous high frequency electrical stimulation to the thalamus via the
implanted electrodes. This form of stimulation helps the thalamus
"rebalance" the control messages in the movement control centers of the
brain. Patients may turn the pulse generator off and on by passing a
hand-held magnet over the device. The batteries that power the pulse
generator need to be surgically replaced every 3 to 5 years.
Adverse events due to thalamic stimulation are generally mild. The
severity of complications and side effects usually correlate with the
intensity of stimulation. The possible complications of DBS include mild
speech impairment (dysarthria), weakness on one or both sides of the body,
or disturbance of normal balance (dysequilibrium). In most patients,
unusual sensations (paresthesias) such as numbness or tingling in the head
and hands may occur after surgery; however, these sensations typically
resolve with ongoing adjustment of the stimulator settings. About six
percent of patients experience marked speech impairment or permanent,
though tolerable, paresthesias. To date, deep brain stimulation has been
performed on very few patients with dystonia. Generally, moderate
improvement has been reported. Several clinical centers are currently
conducting studies on DBS of the pallidum in patients with dystonia.
Another feasibility study is being performed in those patients with
intractable dystonia. See E-MOVE Article: Surgery for Dystonia.
Myectomy (Myotomy)
Selective myectomy or myotomy is a surgical procedure during which a
portion of an overactive muscle is removed. This procedure was a common
treatment for blepharospasm; however, with the advent of botulinum toxin
treatment, selective myectomies are only rarely performed.
Ramisectomy and Rhizotomy
Ramisectomy and rhizotomy are surgical procedures that involve the
cutting of a nerve(s) that innervates an overactive muscle. These types
of surgeries are rarely performed; however, they may be effective in
certain, properly chosen patients. They are most commonly performed on
patients with cervical dystonia who have developed resistance to BTX-A.
Possible adverse effects include permanent muscle weakness as well as
difficulty swallowing. See E-MOVE Article Dystonia surgery (AAN report).
Peripheral Denervation
During selective peripheral denervation (SPD) or the Bertrand Procedure,
nerves are removed at the point where they enter the selected, hyperactive
muscle. Nerve supply (innervation) to uninvolved muscles is maintained.
This procedure may be an option for some patients who were not successfully
treated or have not responded to toxin therapy.
Other Approaches to Treatment
Stretching exercises may be important for maintaining or recovering range
of motion for affected joints (such as of the arms, legs, etc.). For
example, a regular program of stretching exercises may assist affected
individual in regaining full range of motion after a BTX injection has
weakened a dystonic muscle.
Some patients use so-called "sensory tricks" to temporarily relieve their
symptoms. These frequently involve touching or stroking a particular spot
on the skin. The exact mechanism of relief obtained by these "sensory
tricks" is not understood. It is possible that skin stimulation may
interrupt abnormal nerve impulses that cause muscle overactivity. In
addition, in some patients, certain types of braces may provide the same
stimulation and be equally effective.
A number of clinical trials have studied the use of biofeedback techniques
for the treatment of individuals with dystonia. Some patients have
benefited; however, in most patients, no long term, clear-cut improvement
has been demonstrated. Clinical trials have demonstrated that
manipulation-based therapies (chiropractic, etc.) have not been
effective for people with dystonia; however, some patients report that
they obtain some benefit from these techniques. Practitioners are advised
not to use force, but to assist their patients in using their own resources
to compensate for postural abnormalities.
Dystonia DYT1 Gene FAQ
Summary of Nature Genetics article. Edited: June 3, 1999 (JEB)
In the September 1997 issue of Nature Genetics, scientists announced the
discovery of the gene responsible for most cases of early-onset dystonia,
the most common form of hereditary dystonia. This type of dystonia, also
known as generalized dystonia or idiopathic torsion dystonia (ITD), is
a neurologic movement disorder characterized by twisting or turning
movements and abnormal postures. The gene, called DYT1, encodes for a
protein known as torsinA. The exact function of torsinA is not known.
Frequently Asked Questions about the Discovery of the Early-onset
Dystonia Gene. (These questions were answered by Dr. Mitchell F. Brin,
Director Movement Disorder Center, Mount Sinai Medical Center, New York,
NY, US)
I am affected by dystonia, as are other members of my family. What does
the discovery of the DYT1 gene mean to me?
The discovery that the DYT1 gene encodes for torsinA has several important
implications for those affected by early-onset dystonia. You and other
members of your family may now be able to receive an accurate, direct
genetic test to determine if you are a carrier of this gene. Such a test
may benefit individuals who have symptoms associated with dystonia as well
as those who do not have symptoms but have a relative with dystonia. For
those individuals with symptoms, a positive test for the DYT1 gene may
assist their neurologist in confirming the diagnosis. For relatives of
affected individuals, this genetic test may provide important information
as to whether or not they are also carriers of the DYT1 gene. This may
help to establish their risk for developing symptoms associated with
dystonia.
The tendency or "predisposition" for developing any of the various types
of dystonia is controlled or regulated by the interaction of many genes.
Therefore, negative test results do not necessarily mean that individuals
do not have another gene that may contribute to the development of dystonia.
The discovery of the DYT1 gene will accelerate research into the causes
of early-onset dystonia. When scientists understand more fully how
defective genes work and interact to cause the symptoms of dystonia, they
may be able to design treatments that directly address these problems.
It is important to remember that finding the gene for a condition is only
the first step in the long process of developing better treatments.
However, with this information in hand, the logical direction for research
into treatments becomes clearer.
What is a genetic test?
A genetic test is a particular kind of laboratory test, usually done on
cells from the blood of the person being tested. The goal of the test is
to determine the presence or absence of particular changes in the genes
of the person being tested; aid in the diagnosis of a disease; or determine
if a person is a carrier of a particular disease gene. A direct test looks
for change(s) in the actual gene in question. This type of testing is more
accurate than the linkage test, which tests for chromosome differences
usually close in location to the disease gene. Until now, the only genetic
test for early-onset dystonia was a linkage test. A direct test is now
possible for one form of early-onset dystonia associated with the DYT1
gene.
What are genes?
Genes are long molecules composed of the chemical DNA and are found in
the nucleus of each cell. Genes perform two important functions. Firstly,
each gene is the recipe, blueprint, or code for building a particular
protein within the cell. Because proteins do all their work inside a cell,
a mistake in the blueprint for any one of these proteins may have serious
consequences for the functioning of that cell. Early-onset dystonia is
caused by a mistake in the gene that contains the code for the protein
called torsinA. The exact role of torsinA in brain cells is not known.
Secondly, genes are the material of inheritance–copied and passed from
parent to child–they ensure that offspring arise from a combined set of
blueprints from the parents. Genes are linked together to form even longer
structures known as chromosomes. Almost every human cell contains exactly
46 chromosomes or 23 pairs. Each chromosome comprises hundreds or
thousands of genes strung together. The DYT1 gene is located on the long
arm of chromosome 9 (9q34).
What is a genetic disorder?
A genetic disorder is a condition that occurs as the result of mistakes
or changes in the code or of a gene. These changes, called new mutations,
occur before conception during sperm or egg production. When this mutation
occurs, the parent is not affected by the disorder; however, the child
who receives the genes in that sperm or egg may be affected. As the
developing fetus grows, the mutated or altered gene is usually copied
exactly (i.e., in its mutated or changed form). Therefore, each cell in
the body carries the mutated gene. This includes the sperm or egg cells
produced by this individual. This means that this individual may pass on
the gene to his or her children. A disorder that occurs as the result of
a mutated gene that can be "transmitted" is occasionally called a
heritable disorder. Early-onset dystonia is one type of heritable
dystonia.
What is the DYT1 mutation and how did it arise?
The DYT1 mutation that causes early-onset dystonia is a deletion of three
nucleotides, called GAG. Nucleotides are the molecular building blocks
of DNA. This relatively minute change in the torsinA blueprint apparently
causes critical changes in the function of the protein, and in some cases,
ultimately leads to the symptoms of dystonia. Therefore, individuals who
have this mutation are carriers of the DYT1 GAG deletion.
Most cases of early-onset dystonia are not due to new mutations, but rather
to accurate or "faithful" copying and inheritance of a gene mutation that
occurred many generations in the past. Many cases of this type of dystonia
are found among the Ashkenazi Jewish population (Jews who trace their
ancestry back to Central and Eastern Europe). In addition, non-Ashkenazic
individuals with the disorder carry the same mutation. This mutation is
also seen in non-Ashkenazic Caucasians, African Americans, Asians, and
other populations.
What are the other types of heritable dystonia?
There are other types of heritable dystonia, each of which is
distinguished by the gene responsible for the disorder. For example, the
gene for dopa-responsive dystonia (DRD) has been identified and well
characterized. The gene locations for several other dystonias have also
been determined, including that for X-linked parkinsonism on the X
chromosome. Another disease gene located on chromosome 8 codes for a type
of dystonia observed predominantly in the Amish and Mennonite populations.
Other genetic forms of dystonia are summarized in the table Dystonia:
Molecular Classification. If a gene test is negative, it is possible that
another genetic form is present but not the one tested.
Do both parents need to pass on the gene mutation in order for a child
to develop dystonia?
No, not usually. Early-onset dystonia is known as a dominant disorder.
This means that only one copy of the abnormal gene is needed in order for
an individual to inherit the potential to show symptoms. Some other
genetic disorders, but not heritable dystonias (except for rare cases of
DRD) are termed recessive. This means that two abnormal copies of the
abnormal gene are needed before a person develops the disorder.
Early-onset dystonia is also an autosomal disorder, meaning the gene is
not carried on the chromosomes that determine an individual gender or sex
(i.e., the X or Y chromosomes). Consequently, individuals of both sexes
may develop the disorder and either parent may pass on the gene to their
offspring. In contrast, an X-linked recessive gene is more likely to be
expressed in males. X-linked dominant genes are usually lethal in males.
If I have a mutation in my DYT1 gene, does that mean that I will get dystonia?
It is possible that you will get dystonia, but not necessarily. For reasons
scientists do not yet understand, only 30 to 40% of those with the abnormal
DYT1 gene develop dystonia. There is no way yet to predict whether a person
with the abnormal gene will develop symptoms of the disorder.
Should I be tested for the dystonia gene?
The decision to get a genetic test is a personal decision and one that
should not be made lightly. You may want to consider these factors while
making your decision:
Do you have symptoms of dystonia?
Individuals who already have symptoms of dystonia, but who have not yet
been definitively diagnosed, may benefit from genetic testing. A positive
result may allow their physician to make a definitive diagnosis and allow
individuals with dystonia to finally identify a cause of their symptoms.
A negative test result does not mean that you do not have an inherited
form of dystonia. It simply means that you do not carry the DYT1 gene
abnormality.
Does a family member have early-onset dystonia?
If another member of your family has early-onset dystonia, you have
probably asked yourself whether you will also develop symptoms. Your test
results may provide you with the additional knowledge. A positive result
only means that you may develop symptoms and most individuals who have
the gene do not develop the symptoms of dystonia. Moreover, a negative
result does not necessarily mean that you are "dystonia free." There are
other forms of inherited dystonia.
Are there professionals who can help me understand the issues that are
involved in genetic testing?
A genetic counselor is a person trained in both the science and the
psychological issues involved in genetic testing. A genetic counselor can
help you explore the benefits and downsides of getting tested, as well
as help you understand what the results mean and do not mean. If you are
thinking of undergoing a genetic test, you should plan to talk with a
genetic counselor. In fact, most centers that do genetic testing require
consultation with a genetic counselor before the test is performed. These
centers have genetic counselors who are available for appointments.
Where can I get a genetic test if I want one?
Genetic testing is available at a number of laboratories. The Movement
Disorders Program at Mount Sinai Medical Center in New York City sends
its patients blood samples to the Massachusetts General Neurogenetics DNA
Diagnostic Laboratory in Boston, MA. The telephone number for the
laboratory is (617) 726-5721.
For a listing of genetic counselors in your area, contact:
National Society of Genetic Counselors (NSGC)
www.nsgc.org
For additional information on a variety of genetic issues, contact:
The Genetic Alliance
www.geneticalliance.org
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